CN112165939A - Combination therapy - Google Patents

Abstract

Provided herein are methods of treating diseases, such as cancer, using combination therapy. In certain embodiments, the method comprises administering to the patient an effective amount of a phosphoinositide-3-kinase (PI3K) inhibitor and an effective amount of a Bruton's Tyrosine Kinase (BTK) inhibitor.

Description

Combination therapy

Cross Reference to Related Applications

This application claims the benefit of U.S. provisional application No. 62/646,314 filed on 21/3/2018, which is incorporated by reference into the disclosure of this application.

Technical Field

Provided herein are methods of treating diseases using combination therapies for treating proliferative diseases, including cancer, autoimmune diseases, and inflammatory diseases. In certain embodiments, the method comprises administering to the patient an effective amount of a phosphoinositide-3-kinase (PI3K) inhibitor and an effective amount of a Bruton's Tyrosine Kinase (BTK) inhibitor.

Background

Phosphoinositide-3-kinase (PI3K) plays multiple roles in normal tissue physiology, with p110 α having a specific role in cancer growth and p110 β in integrin α_Πβ₃Mediated thrombosis, while p110 γ has a specific role in inflammation, rheumatoid arthritis and other chronic inflammatory states. Inhibitors of PI3K have therapeutic potential in the treatment of various proliferative diseases, including cancer.

Bruton's Tyrosine Kinase (BTK) inhibitors are a class of drugs that inhibit Bruton's Tyrosine Kinase (BTK), which is a member of the Tec kinase family, and have very unique roles in B cell antigen receptor (SCR) signaling.

There remains a need to develop effective doses and dosing regimens for administering a PI3K inhibitor and a BTK inhibitor in combination with a second agent for the treatment, prevention and management of various proliferative diseases, including cancer, autoimmune and/or inflammatory diseases.

Disclosure of Invention

Disclosed herein is a method of treating or preventing cancer, comprising administering to a patient in need thereof:

(i) about 30mg, about 45mg or about 60mg of a compound of formula (I):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

x, Y and Z are each independently N or CR^XProvided that at least two of X, Y and Z are nitrogen atoms; wherein R is^XIs hydrogen or C_1-6An alkyl group;

R¹and R²Each independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a Wherein each R^1a、R^1b、R^1cAnd R^1dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^1bAnd R^1cTogether with the N atom to which they are attached form a heterocyclyl;

R³and R⁴Each independently is hydrogen or C_1-6An alkyl group; or R³And R⁴Are connected together to form a bond, C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene or C_2-6A heteroalkenylene group;

R^5ais (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heteroA cyclic group; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) or- (CR^5fR^5g)_n-a heteroaryl group;

R^5dand R^5eEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5fAnd R^5gEach independently of the other is (a) hydrogenOr halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1c(ii) a or-S (O)₂NR^1bR^1c(ii) a Or (d) when one is present R^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd

R^5gtogether with the carbon atom to which they are attached form C_3–10Cycloalkyl or heterocyclyl;

R⁶is hydrogen, C_1-6Alkyl, -S-C_1-6Alkyl, -S (O) -C_1-6Alkyl or-SO₂–C_1-6An alkyl group;

m is 0 or 1; and is

n is 0, 1, 2, 3 or 4;

wherein R is¹、R²、R³、R⁴、R⁶、R^X、R^1a、R^1b、R^1c、R^1d、R^5a、R^5b、R^5c、R^5d、R^5e、R^5fAnd R^5gEach alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl group of (a) is optionally substituted with one, two, three, four, or five substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one, two, three or four substituents Q^aSubstituted; and (c) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cand-S (O)₂NR^bR^cWherein each R is^a、R^b、R^cAnd R^dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is further optionally substitutedOne, two, three or four substituents Q ^aSubstituted; or (iii) R^bAnd R^cTogether with the N atom to which they are attached form a heterocyclic group which is further optionally substituted by one, two, three or four substituents Q^aSubstituted;

wherein each Q^aIndependently selected from (a) oxo, cyano, halo and nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl; and (c) -C (O) R^e、–C(O)OR^e、–C(O)NR^fR^g、–C(NR^e)NR^fR^g、–OR^e、–OC(O)R^e、–OC(O)OR^e、–OC(O)NR^fR^g、–OC(＝NR^e)NR^fR^g、–OS(O)R^e、–OS(O)₂R^e、–OS(O)NR^fR^g、–OS(O)₂NR^fR^g、–NR^fR^g、–NR^eC(O)R^h、–NR^eC(O)OR^h、–NR^eC(O)NR^fR^g、–NR^eC(＝NR^h)NR^fR^g、–NR^eS(O)R^h、–NR^eS(O)₂R^h、–NR^eS(O)NR^fR^g、–NR^eS(O)₂NR^fR^g、–SR^e、–S(O)R^e、–S(O)₂R^e、–S(O)NR^fR^gand-S (O)₂NR^fR^g(ii) a Wherein each R^e、R^f、R^gAnd R^hIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^fAnd R^gTogether with the N atom to which they are attached form a heterocyclyl;

wherein two substituents Q adjacent to each other are optionally topographicallyTo C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and

(ii) about 160mg or about 320mg BGB-3111 or a pharmaceutically acceptable salt thereof, wherein a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, is administered to the subject once daily; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl or heteroaryl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–S(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c。

In some embodiments, R^5aAnd R^5bEach independently is (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c。

In some embodiments, R^5aAnd R^5bEach is methyl optionally substituted with one, two or three halo. In some embodiments, n is 1. In some embodiments, n is 1 and R^5fAnd R^5gEach is hydrogen. In some embodiments, n is 0. In some embodiments, m is 0.

The synthesis of compounds of formula (I) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In some embodiments, the compound of formula (I) is a compound of formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^7a、R^7b、R^7c、R^7dand R^7eEach independently is (a) hydrogen, cyano, halo, or nitro; (b) c _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; or (c) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cor-S (O)₂NR^bR^c(ii) a Or

R^7a、R^7b、R^7c、R^7dAnd R^7eTwo of which are adjacent to each other form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting.

The synthesis of compounds of formula (XI) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In some embodiments, the compound of formula (I) is compound I:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound II:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound III:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound IV:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound V:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound VI:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound VII:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound VIII:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound IX:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the compound of formula (I) is compound X:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

In some embodiments, the cancer treated is a hematologic malignancy. In some embodiments, the cancer treated is a B cell malignancy. In some embodiments, the cancer treated is Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), acute monocytic leukemia (AMoL), Chronic Lymphocytic Leukemia (CLL), high risk Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, burkitt's lymphoma, non-burkitt high grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, primary lymphoblastic large cell lymphoma, secondary lymphoblastic leukemia, secondary lymphoblastic lymphoma, secondary lymphoblastic, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma or lymphomatoid granulomatosis. In some embodiments, the cancer treated is chronic lymphocytic leukemia or non-hodgkin's lymphoma. In some embodiments, the cancer treated is non-hodgkin's lymphoma, and the non-hodgkin's lymphoma is diffuse large B-cell lymphoma (DLBCL). In some embodiments, the cancer treated is relapsed refractory diffuse large B-cell lymphoma (r/r DLBCL). In some embodiments, the diffuse large B-cell lymphoma is activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) or germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL).

In some embodiments, about 30mg of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, is administered to the subject; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, about 45mg of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, is administered to the subject; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, about 60mg of a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, is administered to the subject; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, about 160mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, about 320mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject. In some embodiments, BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to a subject once daily or twice daily. In some embodiments, BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to a subject once daily. In some embodiments, BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to a subject twice daily. In some embodiments, about 160mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject twice daily. In some embodiments, about 320mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject once per day.

In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation thereof, is administered simultaneously, substantially simultaneously, or sequentially in any order; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and BGB-3111 or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, is administered simultaneously or substantially simultaneously; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and BGB-3111 or a pharmaceutically acceptable salt thereof.

In some embodiments, the compounds of formula (I), or enantiomers, mixtures of two or more diastereomers, or isotopic variations thereof, are administered sequentially; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and BGB-3111 or a pharmaceutically acceptable salt thereof.

In some embodiments, a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, is administered prior to BGB-3111, or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variation thereof, is administered after BGB-3111, or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is formulated as a tablet or capsule. In some embodiments, BGB-3111, or a pharmaceutically acceptable salt thereof, is formulated as a tablet or capsule. In some embodiments, a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is co-formulated with BGB-3111 or a pharmaceutically acceptable salt thereof.

Disclosed herein is a pharmaceutical composition comprising compound I:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound II:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound III:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound IV:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound V:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound VI:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound VII:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound VIII:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound IX:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a pharmaceutical composition comprising compound X:

an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound I, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound II, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound III, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound IV, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound V, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound VI, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound VII, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound VIII, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound IX, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Disclosed herein is a method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of a pharmaceutical composition comprising compound X, an isotopic variant thereof, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

Is incorporated by reference

All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference.

Drawings

The novel features of the invention are set forth with particularity in the appended claims. A better understanding of the features and advantages of the present invention will be obtained by reference to the following detailed description that sets forth illustrative embodiments, in which the principles of the invention are utilized, and the accompanying drawings of which:

figure 1 shows the% growth inhibition in DB cells versus the concentration of compound I as measured in the applite assay.

FIG. 2 shows the% growth inhibition in DOHH-2 cells versus the concentration of compound I as measured in the ATPLite assay.

Figure 3 shows the% growth inhibition in HT cells versus the concentration of compound I as measured in the applite assay.

FIG. 4 shows% growth inhibition in NU-DHL-1 cells versus concentration of compound I as measured in the ATPLite assay.

FIG. 5 shows the% growth inhibition in OCI-Ly19 cells versus the concentration of Compound I as measured in the ATPLite assay.

FIG. 6 shows the% growth inhibition in OCI-Ly3 cells versus the concentration of Compound I as measured in the ATPLite assay.

Figure 7 shows the% growth inhibition in Pfeiffer cells versus the concentration of compound I as measured in the applite assay.

FIG. 8 shows the% growth inhibition in SU-DHL-10 cells relative to the concentration of Compound I as measured in the ATPLite assay.

FIG. 9 shows the growth inhibition of Compound I in the cell lines tested (GI)₅₀)。

Figure 10 shows the% growth inhibition of compound I in the cell lines tested.

Detailed Description

Described herein are pharmaceutical compositions comprising i) a PI3K inhibitor and ii) a BTK inhibitor. In some cases, the pharmaceutical compositions described herein can be used to treat a disease or disorder, such as cancer. Also described herein are methods of treating diseases and disorders, such as cancer, with a combination of i) a PI3K inhibitor and ii) a BTK inhibitor.

To facilitate understanding of the disclosure described herein, several terms are defined below.

Generally, the nomenclature used herein and the laboratory procedures in organic chemistry, medicinal chemistry, and pharmacology described herein are those well known and commonly employed in the art. Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The term "subject" refers to an animal, including but not limited to a primate (e.g., human), cow, pig, sheep, goat, horse, dog, cat, rabbit, rat, or mouse.

Definition of

The terms "subject" and "patient" are used interchangeably herein with reference to, for example, a mammalian subject, such as a human subject (in one embodiment, a human).

The terms "treat" and "treating" are intended to include reducing or eliminating a disorder, disease, or condition, or one or more symptoms associated with the disorder, disease, or condition; or to reduce or eradicate the cause of the disorder, disease, or condition itself.

The terms "prevent" and "prevention" are intended to include delaying and/or preventing the onset of a disorder, disease or condition and/or its attendant symptoms; preventing the subject from becoming afflicted with a disorder, disease, or condition; or reducing the risk of a subject suffering from a disorder, disease, or condition.

The terms "therapeutically effective amount" and "effective amount" are intended to include an amount of a compound that, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of the disorder, disease, or condition being treated. The term "therapeutically effective amount" or "effective amount" also refers to an amount of a compound that is sufficient to elicit the biological or medical response of a biomolecule (e.g., protein, enzyme, RNA or DNA), cell, tissue, system, animal or human that is being sought by a researcher, veterinarian, medical doctor or clinician.

The terms "pharmaceutically acceptable carrier," "pharmaceutically acceptable excipient," "physiologically acceptable carrier," and "physiologically acceptable excipient" refer to a pharmaceutically acceptable material, composition, or vehicle, such as a liquid or solid filler, diluent, solvent, or encapsulating material. In one embodiment, each component is "pharmaceutically acceptable" in the sense of being compatible with the other ingredients of the pharmaceutical formulation and is suitable for use in contact with the tissues or organs of humans and animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications, commensurate with a reasonable benefit/risk ratio. See Remington, The Science and Practice of Pharmacy, 21 st edition, Lippincott Williams & Wilkins, Philadelphia, PA, 2005; handbook of Pharmaceutical Excipients, 5 th edition, compiled by Rowe et al, The Pharmaceutical Press and The American Pharmaceutical Association, 2005; and Handbook of Pharmaceutical Additives, 3 rd edition, compiled by Ash and Ash, Gower Publishing Company, 2007; pharmaceutical preparation and Formulation, 2 nd edition, edited by Gibson, CRC Press LLC: Boca Raton, FL, 2009.

The terms "about" and "approximately" mean within an acceptable error of a particular value, as determined by one of ordinary skill in the art, which depends in part on how the value is measured or determined. In certain embodiments, the terms "about" and "approximately" mean within 1, 2, 3, or 4 standard deviations. In certain embodiments, the term "about" or "approximately" means within 50%, 20%, 15%, 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%, or 0.05% of a given value or range.

The terms "active ingredient" and "active agent" refer to a compound that is administered to a subject alone or in combination with one or more pharmaceutically acceptable excipients to treat, prevent, or alleviate one or more symptoms of a disorder, disease, or condition. As used herein, the "active ingredient" and "active substance" may be optically active isomers of the compounds described herein.

The terms "drug," "therapeutic agent," and "chemotherapeutic agent" refer to a compound or pharmaceutical composition thereof that is administered to a subject to treat, prevent, or alleviate one or more symptoms of a disorder, disease, or condition.

The terms "naturally-occurring" and "native" when used in conjunction with biological materials, such as nucleic acid molecules, polypeptides, host cells, and the like, refer to materials found in nature that have not been manipulated by man. Similarly, "non-naturally occurring" or "non-natural" refers to a substance that is not found in nature or that has been structurally modified or synthesized by man.

The term "PI 3K" refers to phosphatidylinositol 3-kinase or variants thereof, which is capable of phosphorylating the inositol ring of PI at the D-3 position. The term "PI 3K variant" is intended to include proteins that are substantially homologous to native PI3K, i.e., proteins having one or more naturally or non-naturally occurring amino acid deletions, insertions, or substitutions as compared to the amino acid sequence of native PI3K (e.g., PI3K derivatives, homologs, and fragments). The amino acid sequence of the PI3K variant is at least about 80% identical, at least about 90% identical, or at least about 95% identical to native PI 3K. Examples of PI3K include, but are not limited to, p110 α, p110 β, p110 γ, PI3K-C2 α, PI3K-C2 β, PI3K-C2 γ, Vps34, mTOR, ATM, ATR, and DNA-PK. See, Fry, biochem, biophysis, acta 1994,1226, 237-268; vanhaaesebroeck and Waterfield, Exp. cell. Res.1999,253, 239-254; and Fry, Breast Cancer Res.2001,3, 304-312. PI3K is classified into at least four categories. Class I includes p110 α, p110 β, p110 and p110 γ. Class II includes PI3K-C2 α, PI3K-C2 β, and PI3K-C2 γ. Class III includes Vps 34. Class IV includes mTOR, ATM, ATR, and DNA-PK. In certain embodiments, PI3K is a class I kinase. In certain embodiments, PI3K is p110 α, p110 β, p110, or p110 γ. In certain embodiments, PI3K is a variant of a class I kinase. In certain embodiments, PI3K is a p110 α mutant. Examples of P110 α mutants include, but are not limited to, R38H, G106V, K111N, K227E, N345K, C420R, P539R, E542K, E545A, E545G, E545K, Q546K, Q546P, E453Q, H710P, I800L, T1025S, M10431, M1043V, H1047L, H1047R, and H1047Y (Ikenoue et al, Cancer Res.2005,65, 4562-. In certain embodiments, PI3K is a class II kinase. In certain embodiments, PI3K is PI3K-C2 α, PI3K-C2 β, or PI3K-C2 γ. In certain embodiments, PI3K is a class III kinase. In certain embodiments, PI3K is Vps 34. In certain embodiments, PI3K is a class IV kinase. In certain embodiments, PI3K is mTOR, ATM, ATR, or DNA-PK.

As used herein, "BTK" refers to bruton's tyrosine kinase. BTK belongs to the Tec tyrosine kinase family (Vetrie et al, Nature 361:226-233, 1993; Bradshaw, Cell Signal.22:1175-84, 2010). BTK is expressed predominantly in most hematopoietic cells such as B cells, mast cells and macrophages (Smith et al, J.Immunol.152:557-565,1994) and is localized in bone marrow, spleen and lymph node tissues. BTK plays an important role in the B-cell receptor (BCR) and FcR signaling pathways involved in B-cell development, differentiation (Khan, immunol. res.23:147,2001). BTK inhibitors may be selected from compounds disclosed in the following references: U.S. Pat. nos. 8,084,620B 2; 7,514,444B 2; 7,718,662B 1; and 7,393,848B 1; U.S. publication nos. 2016/0083392a 1; 2015/0005277A 1; 2015/0259354A 1; 2012/053189A 1; 2010/254905A 1; 2008/0139582A 1; 2012/0077832A 1; 2012/0232054A 1; 2012/082702A 1; 2010/0160303a1, 2012/129852a 1; 2006/0178367A 1; 2006/0183746A 1; 2012/040961A 1; 2010/144705A 1; 2012/0028981A 1; 2012/058996A 1; 2009/0318448A 1; 2010/0016301A 1; 2009/105209A 1; 2010/0222325A 1; and 2010/0004231A 1; international publication nos. wo 2011/153514; WO 2011/046964; WO 2010/009342; WO 2008/121742; WO 2008/054827; WO 2007/087068; WO 2011/090760; WO 2010/028236; WO 2009/158571; WO 2009/051822, WO 2010/123870; WO 2010/126960; WO 2011/162515; WO 2012/135801; WO 2011/152351; WO 2007/136790a 2; WO 2002/050071; WO 2008/116064; WO 2010/011837; WO 2011/159857, WO 2011/019780, WO 2011/029043; WO 2011/029046; WO 2005/005429; WO 2005/014599; WO 2005/047290; WO 2006/053121; WO 2008/033834; WO 2008/033858; WO 2006/099075; WO 2008/033854; WO 2008/033857; WO 2009/039397, WO 2009/137596; WO 2010/056875; WO 2010/068788; WO 2010/068806; WO 2010/068810, WO 2011/140488; WO 2012/030990; WO 2012/031004; WO 2005/011597; WO 2008/045627; WO 2008/144253, WO 2007/140222, WO 2013/008095, WO 2012/170976a2, WO 2012/135944a 1; WO 2010/065898a 2; WO 2012/158795a 1; WO 2012/158764a 1; WO 2012/158810a 1; WO 2012156334a 1; WO 2012020008; WO 2010122038; WO 2010006970; WO 2010006947; WO 2010000633; WO 2009077334; WO 2009098144, WO 2006065946; WO 2007027594; WO 2007027729 and EP 2068849. BTK inhibitors may also be selected from ibrutinib, BGB-3111, CC-292(AVL-292), ACP 196(Acalabrutinib), CNX-774, CGI1746, LFM-A13, CNX-774, ONO-4059, RN486 CPI-0610, DUAL946, GSK525762, I-BET151, JQ1, OTX015, PFI-1, RVX-208, RVX2135, TEN-010, and combinations thereof. In one embodiment, the BTK inhibitor is ibrutinib or BGB-3111.

The terms "synergistic," "synergy," and "synergistic" as used herein refer to a therapeutic combination (e.g., using a PI3K inhibitor of formula (I) and a BTK inhibitor) that is more effective than the expected additive effect of any two or more monotherapies. For example, the synergistic effect of the combination of therapies allows for the use of lower doses of one or more of the treatments and/or allows for less frequent administration of the treatments to a subject. The ability to use lower doses of treatment and/or less frequently administer treatment reduces the toxicity associated with administering treatment to a subject without reducing the efficacy of the treatment in preventing, managing, treating, or ameliorating a given disease, such as an autoimmune disease, an inflammatory disease, or a cancer, including but not limited to chronic lymphocytic leukemia or non-hodgkin's lymphoma. In addition, synergistic effects may result in improved efficacy of the treatment in preventing, controlling, treating or ameliorating a given disease, such as an autoimmune disease, an inflammatory disease or cancer, including but not limited to chronic lymphocytic leukemia or non-hodgkin's lymphoma. Finally, the synergistic effect of the combination of therapies may avoid or reduce the adverse or unwanted side effects associated with the use of any monotherapy. The "synergistic" or "synergistic" effect of a combination can be determined herein by the methods of Chou et al and/or Clarke et al. See, Ting-Chao Chou, the clinical Basis, Experimental Design, and formulated Simulation of synergy and anticancer in Drug Combination Studies, Pharmacol Rev 58:621-681(2006), and Clarke et al, esses in Experimental Design and end analysis in the study of Experimental cytoxic agents in vivo in biological in culture camera and other models, Breast Cancer Research and Treatment 46:255-278(1997), which is incorporated by reference for determining the "synergy" or "synergistic" effect of a Combination.

The term "isotopic variant" refers to a compound that contains an unnatural proportion of an isotope at one or more atoms that make up the compound. In certain embodiments, an "isotopic variant" of a compound contains a non-natural proportion of one or more isotopes, including but not limited to hydrogen (h) ((ii))¹H) Deuterium (1)²H) Tritium (a)³H) Carbon-11 (C)¹¹C) Carbon-12 (C)¹²C) Carbon-13 (C)¹³C) Carbon-14 (C)¹⁴C) Nitrogen-13 (¹³N), nitrogen-14 (¹⁴N), nitrogen-15 (¹⁵N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), oxygen-16 (¹⁶O), oxygen-17 (¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F) Fluorine-18 (¹⁸F) Phosphorus-31 (³¹P), phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-35 (³⁵S), sulfur-36 (³⁶S), chloro-35 (³⁵Cl), chloro-36 (³⁶Cl), chloro-37 (³⁷Cl), bromo-79 (⁷⁹Br), bromo-81 (⁸¹Br), iodine-123 (¹²³I) Iodine-125 (¹²⁵I) Iodine-127 (¹²⁷I) Iodine-129 (¹²⁹I) And iodine-131 (¹³¹I) In that respect In certain embodiments, an "isotopic variant" of a compound is in a stable form, i.e., non-radioactive. In certain embodiments, an "isotopic variant" of a compound contains a non-natural proportion of one or more isotopes, including but not limited to hydrogen (h) ((ii))¹H) Deuterium (1)²H) Carbon-12 (C)¹²C) Carbon-13 (C)¹³C) Nitrogen-14 (¹⁴N), nitrogen-15(¹⁵N), oxygen-16 (¹⁶O), oxygen-17 ( ¹⁷O), oxygen-18 (¹⁸O), fluorine-17 (¹⁷F) Phosphorus-31 (³¹P), sulfur-32 (³²S), sulfur-33 (³³S), sulfur-34 (³⁴S), sulfur-36 (³⁶S), chloro-35 (³⁵Cl), chloro-37 (³⁷Cl), bromo-79 (⁷⁹Br), bromo-81 (⁸¹Br and iodine-127: (¹²⁷I) In that respect In certain embodiments, an "isotopic variant" of a compound is in a non-stable form, i.e., radioactive. In certain embodiments, an "isotopic variant" of a compound contains a non-natural proportion of one or more isotopes, including but not limited to tritium (tritium: (ii))³H) Carbon-11 (C)¹¹C) Carbon-14 (C)¹⁴C) Nitrogen-13 (¹³N), oxygen-14 (¹⁴O), oxygen-15 (¹⁵O), fluorine-18 (¹⁸F) Phosphorus-32 (³²P), phosphorus-33 (³³P), sulfur-35 (³⁵S), chloro-36 (³⁶Cl), iodine-123 (¹²³I) Iodine-125 (¹²⁵I) Iodine-129 (¹²⁹I) And iodine-131 (¹³¹I) In that respect It is to be understood that in the compounds provided herein, for example, any hydrogen can be²H, or for example any carbon may be¹³C, or for example any of the nitrogens may be¹⁵N, or for example any oxygen may be¹⁸O, as long as it is feasible according to the judgment of those skilled in the art. In certain embodiments, an "isotopic variation" of a compound contains a non-natural proportion of deuterium (D).

The term "alkyl" refers to a straight or branched chain saturated monovalent hydrocarbon group, wherein the alkyl group may be optionally substituted with one or more substituents Q as described herein. The term "alkyl" also includes straight or branched chain alkyl groups unless otherwise specified. In certain embodiments, alkyl is a cyclic alkyl having 1 to 20 (C) _1-20) 1 to 15 (C)_1-15) 1 to 10 (C)_1-10) Or 1 to 6 (C)_1-6) A straight-chain saturated monovalent hydrocarbon group of carbon atoms, or a saturated monovalent hydrocarbon group of 3 to 20 (C)_3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 6 (C)_3-6) A branched saturated monovalent hydrocarbon group of carbon atoms. As used herein, straight chain C_1-6And a branch C_3-6Alkyl radicals are also disclosedReferred to as "lower alkyl". Examples of alkyl groups include, but are not limited to, methyl, ethyl, propyl (including all isomeric forms), n-propyl, isopropyl, butyl (including all isomeric forms), n-butyl, isobutyl, sec-butyl, tert-butyl, pentyl (including all isomeric forms), and hexyl (including all isomeric forms). E.g. C_1-6Alkyl refers to a straight chain saturated monovalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated monovalent hydrocarbon group of 3 to 6 carbon atoms.

The term "alkylene" refers to a straight or branched chain saturated divalent hydrocarbon group, wherein the alkylene group may be optionally substituted with one or more substituents Q as described herein. The term "alkylene" includes straight and branched chain alkylene groups unless otherwise specified. In certain embodiments, alkylene is a cyclic alkylene having 1 to 20 (C)_1-20) 1 to 15 (C)_1-15) 1 to 10 (C)_1-10) Or 1 to 6 (C)_1-6) A straight-chain saturated divalent hydrocarbon group of carbon atoms, or 3 to 20 (C) _3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 6 (C)_3-6) A branched saturated divalent hydrocarbon group of carbon atoms. As used herein, straight chain C_1-6And a branch C_3-6Alkylene is also known as "lower alkylene". Examples of alkylene groups include, but are not limited to, methylene, ethylene, propylene (including all isomeric forms), n-propylene, isopropylene, butylene (including all isomeric forms), n-butylene, isobutylene, t-butylene, pentylene (including all isomeric forms), and hexylene (including all isomeric forms). E.g. C_1-6Alkylene means a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms.

The term "heteroalkylene" refers to a straight or branched chain saturated divalent hydrocarbon radical containing one or more heteroatoms in the hydrocarbon chain, each independently selected from O, S and N. E.g. C_1-6Heteroalkylidene refers to a straight chain saturated divalent hydrocarbon group of 1 to 6 carbon atoms or a branched saturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, the heteroalkylene group is a compound having 1 to 20 (C)_1-20) 1 to 15 (C)_1-15) 1 to 10 (C)_1-10) Or1 to 6 (C)_1-6) A straight-chain saturated divalent hydrocarbon group of carbon atoms, or 3 to 20 (C) _3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 6 (C)_3-6) A branched saturated divalent hydrocarbon group of carbon atoms. As used herein, straight chain C_1-6And a branch C_3-6Heteroalkylene groups are also referred to as "lower heteroalkylene groups". Examples of heteroalkylene groups include, but are not limited to, -CH₂O–、–CH₂OCH₂–、–CH₂CH₂O–、–CH₂NH–、–CH₂NHCH₂–、–CH₂CH₂NH–、–CH₂S–、–CH₂SCH₂-and-CH₂CH₂S-. In certain embodiments, heteroalkylene groups may also be optionally substituted with one or more substituents Q as described herein.

The term "alkenyl" refers to a straight or branched chain monovalent hydrocarbon group containing one or more, in one embodiment one, two, three, four or five, and in another embodiment one, carbon-carbon double bond. Alkenyl groups may be optionally substituted with one or more substituents Q as described herein. As understood by those of ordinary skill in the art, the term "alkenyl" also includes groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. As used herein, the term "alkenyl" includes straight and branched chain alkenyl groups, unless otherwise specified. E.g. C_2-6Alkenyl refers to a straight chain unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms, or a branched chain unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, alkenyl is 2 to 20 (C) _2-20) 2 to 15 (C)_2-15) 2 to 10 (C)_2-10) Or 2 to 6 (C)_2-6) A straight-chain monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C)_3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 6 (C)_3-6) A branched monovalent hydrocarbon group of carbon atoms. Examples of alkenyl groups include, but are not limited to, vinyl, propen-1-yl, propen-2-yl, allyl, butenyl, and 4-methylbutenyl.

Term "Alkenylene "refers to a straight or branched chain divalent hydrocarbon group containing one or more carbon-carbon double bonds, in one embodiment one, two, three, four, or five carbon-carbon double bonds, and in another embodiment one carbon-carbon double bond. Alkenylene may be optionally substituted with one or more substituents Q as described herein. Likewise, the term "alkenylene" also includes groups having "cis" and "trans" configurations, or alternatively, groups having "E" and "Z" configurations. As used herein, the term "alkenylene" includes straight and branched chain alkenylene groups unless otherwise specified. E.g. C_2-6Alkenylene refers to a straight chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms, or a branched chain unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, alkenylene is 2 to 20 (C) _2-20) 2 to 15 (C)_2-15) 2 to 10 (C)_2-10) Or 2 to 6 (C)_2-6) A linear divalent hydrocarbon group of carbon atoms, or 3 to 20 (C)_3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 6 (C)_3-6) A branched divalent hydrocarbon group of carbon atoms. Examples of alkenylene include, but are not limited to, ethenylene, allylene, propenylene, butenylene, and 4-methylbutenylene.

The term "heteroalkenylene" refers to a straight or branched divalent hydrocarbon group containing one or more carbon-carbon double bonds, in one embodiment one, two, three, four, or five carbon-carbon double bonds, and in another embodiment one carbon-carbon double bond, and containing one or more heteroatoms in the hydrocarbon chain, each independently selected from O, S and N. Heteroalkenylene may be optionally substituted with one or more substituents Q as described herein. As understood by those of ordinary skill in the art, the term "heteroalkenylene" includes groups having a "cis" or "trans" configuration or mixtures thereof, or alternatively, groups having an "E" or "Z" configuration or mixtures thereof. E.g. C_2-6Heteroalkenylene refers to a straight chain unsaturated divalent hydrocarbon group of 2 to 6 carbon atoms or a branched unsaturated divalent hydrocarbon group of 3 to 6 carbon atoms. In certain embodiments, heteroalkenylene is 2 to 20 (C) _2-20) 2 to 15 (C)_2-15) 2 to 10 (C)_2-10) Or 2 to 6 (C)_2-6) A linear divalent hydrocarbon group of carbon atoms, or 3 to 20 (C)_3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 6 (C)_3-6) A branched divalent hydrocarbon group of carbon atoms. Examples of heteroalkenylene include, but are not limited to, -CH ═ CHO-, -CH ═ CHOCH₂–、–CH＝CHCH₂O–、–CH＝CHS–、–CH＝CHSCH₂–、–CH＝CHCH₂S-or-CH ═ CHCH₂NH–。

The term "alkynyl" refers to a straight or branched chain monovalent hydrocarbon group containing one or more, in one embodiment one, two, three, four or five, and in another embodiment one, three or five carbon-carbon triple bonds. Alkynyl groups may be optionally substituted with one or more substituents Q as described herein. The term "alkynyl" also includes straight and branched chain alkynyl groups unless otherwise specified. In certain embodiments, alkynyl is 2 to 20 (C)_2-20) 2 to 15 (C)_2-15) 2 to 10 (C)_2-10) Or 2 to 6 (C)_2-6) A straight-chain monovalent hydrocarbon group of carbon atoms, or 3 to 20 (C)_3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 6 (C)_3-6) A branched monovalent hydrocarbon group of carbon atoms. Examples of alkynyl groups include, but are not limited to, ethynyl (-C ≡ CH) and propargyl (-CH)₂C ≡ CH). E.g. C_2-6Alkynyl refers to a straight chain unsaturated monovalent hydrocarbon group of 2 to 6 carbon atoms, or a branched chain unsaturated monovalent hydrocarbon group of 3 to 6 carbon atoms.

The term "cycloalkyl" refers to a cyclic, saturated, bridged and/or unbridged monovalent hydrocarbon group, which may be optionally substituted with one or more substituents Q as described herein. In certain embodiments, cycloalkyl has 3 to 20 (C)_3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 7 (C)_3-7) Carbon atoms. Examples of cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, bicyclo [2.1.1]Hexyl, bicyclo [2.2.1]Heptyl, decalinyl, and adamantyl.

The term "cycloalkenyl" refers to a cyclic, unsaturated, non-aromatic bridged and/or non-bridged monovalent hydrocarbon group, which may be optionally substituted with one or more substituents Q as described herein. In certain embodiments, cycloalkenyl groups have 3 to 20 (C)_3-20) 3 to 15 (C)_3-15) 3 to 10 (C)_3-10) Or 3 to 7 (C)_3-7) Carbon atoms. Examples of cycloalkyl groups include, but are not limited to, cyclobutenyl, cyclopentenyl, cyclohexenyl, or cycloheptenyl.

The term "aryl" refers to a monocyclic aromatic group and/or a polycyclic monovalent aromatic group containing at least one aromatic hydrocarbon ring. In certain embodiments, aryl has 6 to 20 (C)_6-20) 6 to 15 (C)_6-15) Or 6 to 10 (C)_6-10) A ring atom. Examples of aryl groups include, but are not limited to, phenyl, naphthyl, fluorenyl, azulenyl, anthracenyl, phenanthrenyl, pyrenyl, biphenyl, and terphenyl. Aryl also refers to bicyclic or tricyclic carbocycles, wherein one ring is aromatic and the other ring may be saturated, partially unsaturated or aromatic, for example, dihydronaphthyl, indenyl, indanyl or tetrahydronaphthyl (tetrahydronaphthyl). In certain embodiments, aryl groups may be optionally substituted with one or more substituents Q as described herein.

The terms "aralkyl" and "arylalkyl" refer to a monovalent alkyl group substituted with one or more aryl groups. In certain embodiments, aralkyl has 7 to 30 (C)_7-30) 7 to 20 (C)_7-20) Or 7 to 16 (C)_7-16) Carbon atoms. Examples of aralkyl groups include, but are not limited to, benzyl, 2-phenylethyl, and 3-phenylpropyl. In certain embodiments, aralkyl is optionally substituted with one or more substituents Q as described herein.

The term "heteroaryl" refers to a monovalent monocyclic aromatic radical or a monovalent polycyclic aromatic radical containing at least one aromatic ring containing one or more heteroatoms in the ring independently selected from O, S, N and P. The heteroaryl group is bonded to the remainder of the molecule through its aromatic ring. Each ring of the heteroaryl group may contain one or two O atoms, one or two S atoms, one to four N atoms, and/or one or two P atoms, provided that the total number of heteroatoms in each ring is four or less, and each ring contains at least one carbon atom. In certain embodiments, heteroaryl groups have 5 to 20, 5 to 15, or 5 to 10 ring atoms. Examples of monocyclic heteroaryl groups include, but are not limited to, furyl, imidazolyl, isothiazolyl, isoxazolyl, oxadiazolyl, oxazolyl, pyrazinyl, pyrazolyl, pyridazinyl, pyridyl, pyrimidinyl, pyrrolyl, thiadiazolyl, thiazolyl, thienyl, tetrazolyl, triazinyl, and triazolyl. Examples of bicyclic heteroaryls include, but are not limited to, benzofuranyl, benzimidazolyl, benzisoxazolyl, benzopyranyl, benzothiadiazolyl, benzothiazolyl, benzothienyl, benzotriazolyl, benzoxazolyl, furopyridinyl, imidazopyridinyl, imidazothiazolyl, indolizinyl, indolyl, indazolyl, isobenzofuranyl, isobenzothienyl, isoindolyl, isoquinolyl, isothiazolyl, naphthyridinyl, oxazolopyridinyl, phthalazinyl, pteridinyl, purinyl, pyridopyridinyl, pyrrolopyridinyl, quinolinyl, quinoxalinyl, quinazolinyl, thiadiazolopyrimidyl, and thienopyridinyl. Examples of tricyclic heteroaryl groups include, but are not limited to, acridinyl, benzindolyl, carbazolyl, dibenzofuranyl, perimidine (perimidinyl), phenanthrolinyl, phenanthridinyl, phenazinyl (phenarasazinyl), phenazinyl, phenothiazinyl, phenoxazinyl, and xanthenyl. In certain embodiments, heteroaryl may also be optionally substituted with one or more substituents Q as described herein.

The terms "heterocyclyl" and "heterocycle" refer to a monovalent monocyclic non-aromatic ring system or a monovalent polycyclic ring system containing at least one non-aromatic ring, wherein one or more non-aromatic ring atoms is a heteroatom independently selected from O, S, N and P; and the remaining ring atoms are carbon atoms. In certain embodiments, heterocyclyl or heterocyclic groups have 3 to 20, 3 to 15, 3 to 10, 3 to 8, 4 to 7, or 5 to 6 ring atoms. The heterocyclic group is bonded to the remainder of the molecule through a non-aromatic ring thereof. In certain embodiments, heterocyclyl is a monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be spirocyclic, fused, or bridged, and wherein the nitrogen or sulfur atom isMay optionally be oxidized, the nitrogen atoms may optionally be quaternized, and some rings may be partially or fully saturated, or aromatic. The heterocyclic group may be attached to the host structure at any heteroatom or carbon atom that results in the production of a stable compound. Examples of such heterocyclic groups include, but are not limited to, aza

A group (azepinyl), a benzodioxanyl group, a benzodioxolyl group, a benzofuranonyl group, a benzopyranonyl group, a benzopyranyl group, a benzotetrahydrofuranyl group, a benzothiophenyl group, a benzothiopyranyl group, a benzoxazinyl group, a β -carbolinyl group, a chromanyl group (chromomonyl group), a cinnolinyl group, a coumarinyl group (coumarinyl group), a decahydroisoquinolinyl group, a dihydrobenzisothiazinyl group, a dihydrobenzisoxazinyl group, a dihydrofuranyl group, a dihydroisoindolyl group, a dihydropyranyl group, a dihydropyrazolyl group, a dihydropyrazinyl group, a dihydropyridinyl group, a dihydropyrimidyl group, a pyrrolinyl group, a dioxolanyl group, a 1, 4-dithianyl group, a furanonyl group, an imidazolidinyl group, an imidazolinyl group, an indolinyl group, an isobenzotetrahydrofuranyl group, an isobenzotetrahydrothienyl group, an isochroman group, an isocoumarinyl group, an isothiazolidinyl group, an isoxazolidinyl group, Morpholinyl, octahydroindolyl, octahydroisoindolyl, oxazolidinonyl, oxiranyl, piperazinyl, piperidinyl, 4-piperidinonyl, pyrazolidinyl, pyrazolinyl, pyrrolidinyl, pyrrolinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydropyranyl, tetrahydrothienyl, thiomorpholinyl (thiazolidinyl), thiazolidinyl, tetrahydroquinolinyl, and 1,3, 5-trithianyl. In certain embodiments, heterocyclyl may also be optionally substituted with one or more substituents Q as described herein.

The terms "halogen", "halide" and "halo" refer to fluorine, chlorine, bromine and/or iodine.

The term "optionally substituted" refers to a group or substituent, such as alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, cycloalkenyl, aryl, aralkyl, heteroaryl-C_1-6Alkyl and heterocyclyl, which may be substituted by one or more substituents Q, each independently selected from, for example, (a) oxo (═ O), halo, cyano (-CN) and nitro (-NO)₂)；(b)C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment with one, two, three, four or five substituents Q^aSubstituted; and (c) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–P(O)R^aR^d、–P(O)(OR^a)R^d、–P(O)(OR^a)(OR^d)、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cand-S (O)₂NR^bR^cWherein each R is^a、R^b、R^cAnd R^dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted with one or more, in one embodiment with one, two, three or fourA substituent Q^aSubstituted; or (iii) R^bAnd R^cTogether with the N atom to which they are attached form a heteroaryl or heterocyclyl group, which is optionally substituted with one or more, in one embodiment with one, two, three or four substituents Q ^aAnd (4) substituting. As used herein, all groups that may be substituted are "optionally substituted" unless otherwise indicated.

In one embodiment, each substituent Q^aIndependently selected from (a) oxo, cyano, halo and nitro; and (b) C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl; and (c) -C (O) R^e、–C(O)OR^e、–C(O)NR^fR^g、–C(NR^e)NR^fR^g、–OR^e、–OC(O)R^e、–OC(O)OR^e、–OC(O)NR^fR^g、–OC(＝NR^e)NR^fR^g、–OS(O)R^e、–OS(O)₂R^e、–OS(O)NR^fR^g、–OS(O)₂NR^fR^g、–NR^fR^g、–NR^eC(O)R^h、–NR^eC(O)OR^h、–NR^eC(O)NR^fR^g、–NR^eC(＝NR^h)NR^fR^g、–NR^eS(O)R^h、–NR^eS(O)₂R^h、–NR^eS(O)NR^fR^g、–NR^eS(O)₂NR^fR^g、–P(O)R^eR^h、–P(O)(OR^e)R^h、–P(O)(OR^e)(OR^h)、–SR^e、–S(O)R^e、–S(O)₂R^e、–S(O)NR^fR^gand-S (O)₂NR^fR^g(ii) a Wherein each R^e、R^f、R^gAnd R^hIndependently is (i) hydrogen, C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (ii) R^fAnd R^gTogether with the N atom to which they are attached form a heteroaryl or heterocyclyl group.

In certain embodiments, "optically active" and "enantiomerically active" refer to a collection of molecules having an enantiomeric excess of no less than about 50%, no less than about 70%, no less than about 80%, no less than about 90%, no less than about 91%, no less than about 92%, no less than about 93%, no less than about 94%, no less than about 95%, no less than about 96%, no less than about 97%, no less than about 98%, no less than about 99%, no less than about 99.5%, or no less than about 99.8%. In certain embodiments, the compounds comprise about 95% or more of the desired enantiomer and about 5% or less of the less preferred enantiomer, based on the total weight of the racemate in question.

In describing optically active compounds, the prefixes R and S are used to denote the absolute configuration of the molecule about its chiral center. (+) and (-) are used to indicate the optical rotation of the compound, i.e., the direction in which the plane of polarized light is rotated by the optically active compound. The (-) prefix indicates that the compound is left-handed, i.e., the compound rotates the plane of polarized light to the left or counterclockwise. The (+) prefix indicates that the compound is right-handed, i.e., the compound rotates the plane of polarized light to the right or clockwise. However, the signs (+) and (-) of optical rotation are not related to the absolute configurations R and S of the molecule.

The phrase "an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, "with the phrase" an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variation of a compound described herein; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug of a compound described herein; or pharmaceutically acceptable salts, solvates, hydrates or prodrugs of enantiomers, mixtures of two or more diastereomers, or isotopic variations of the compounds described herein have the same meaning.

The term "solvate" refers to a complex or aggregate formed from one or more solute molecules (e.g., a compound provided herein) and one or more solvent molecules, which is present in stoichiometric or non-stoichiometric amounts. Suitable solvents include, but are not limited to, water, methanol, ethanol, n-propanol, isopropanol, and acetic acid. In certain embodiments, the solvent is pharmaceutically acceptable. In one embodiment, the complex or aggregate is in a crystalline form. In another embodiment, the complex or aggregate is in a non-crystalline form. When the solvent is water, the solvate is a hydrate. Examples of hydrates include, but are not limited to, hemihydrate, monohydrate, dihydrate, trihydrate, tetrahydrate, and pentahydrate.

Resistance, recurrence or refractory refers to a decrease in the responsiveness of a cancer to treatment, e.g., up to the point in time when the cancer is unresponsive to treatment. The cancer may be resistant at the beginning of the treatment, or may become resistant during the treatment. The term "refractory" may refer to a cancer for which treatment (e.g., chemotherapeutic drugs, biologicals, and/or radiation therapy) has been proven ineffective. Refractory cancer tumors may shrink, but not to the extent that treatment is certainly effective. However, in general, tumors either remain the same size as before treatment (stable disease), or grow (disease progression).

As used herein, the term "responsive" or "to treatment, as well as other forms of the term, refers to the response of a subject to treatment, e.g., monotherapy or combination therapy, with a therapeutic agent, such as a PI3K inhibitor, alone or in combination. Responsiveness to treatment (e.g., treatment with a PI3K inhibitor alone or in combination) can be assessed by comparing the subject's response to treatment using one or more Clinical criteria, such as IWCLL 2008 (for CLL) described in Hallek, m. et al (2008) Blood 111(12):5446- & 5456, such as the Lugano classification described in Cheson, b.d. et al, Journal of Clinical Oncology,32(27) & 3059- & 3067, and the like. Other classifications of reactivity are provided. These standards provide a set of published rules that define when a cancer patient improves ("responds"), remains unchanged ("stabilizes"), or worsens ("progresses") during treatment.

For example, a subject with CLL may be determined to be in Complete Remission (CR) or Partial Remission (PR). For example, according to IWCLL 2008, a subject is considered CR if at least all of the following criteria are met when evaluated after treatment is complete: (i) peripheral blood lymphocytes (assessed by cytometry and differential count) are lower than

(ii) Physical examination shows no hepatomegaly or splenomegaly; (iii) no systemic symptoms; and (iv) a blood count (e.g., neutrophils, platelets, hemoglobin) higher than that described by Hallek, m. According to IWCLL 2008, Partial Remission (PR) of CLL is defined to include one of: (i) blood lymphocytes decreased by 50% or more than pre-treatment values; (ii) detection of a reduction in lymphadenopathy by CT scanning or palpation; or (iii) a reduction of 50% or more of spleen or liver enlargement as detected by CT scanning or palpation compared to pre-treatment; and blood counts according to the values described by Hallek, m. In other embodiments, a subject with CLL is determined to be disease Progression (PD) or Stable Disease (SD). For example, according to IWCLL 2008, a subject is considered PD during or after treatment if at least one of the following criteria is met: (i) progression of lymphadenopathy; (ii) an increase in spleen or liver enlargement of 50% or more compared to pre-treatment, or a de novo hepatomegaly or splenomegaly; (iii) an increase in blood lymphocyte count of 50% or more, at least 5000B lymphocytes per microliter; (iv) conversion to more aggressive histology (e.g., Richter syndrome); or (v) a cytopenia (neutropenia, anemia, or thrombocytopenia) attributable to CLL occurs. According to IWCLL 2008, Stable Disease (SD) of CLL is defined as patients not achieving CR or PR and not yet exhibiting disease progression.

For example, in some embodiments, a subject with CLL responds to treatment with a PI3K inhibitor alone or in combination if at least one criterion of disease progression according to IWCLL is delayed or reduced, e.g., by about 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90% or more. In another example, a subject is responsive to treatment with a PI3K inhibitor alone or in combination if the subject experiences an extended life expectancy, e.g., an increase of about 5%, 10%, 20%, 30%, 40%, 50% or more, compared to the life expectancy predicted in the absence of treatment. In another example, there is a response to treatment with a PI3K inhibitor, alone or in combination, if the subject meets one or more of the following: progression free survival, overall survival extension, or Time To Progression (TTP) extension, e.g., as described by Hallek, m.

Compound (I)

Disclosed herein are PI3K inhibitors of formula (I):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

X, Y and Z are each independently N or CR^XProvided that at least two of X, Y and Z are nitrogen atoms; wherein R is^XIs hydrogen or C_1-6An alkyl group;

R¹and R²Each independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a Wherein each R^1a、R^1b、R^1cAnd R^1dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^1bAnd R^1cTogether with the N atom to which they are attached form a heterocyclyl;

R³and R⁴Each independently is hydrogen or C_1-6An alkyl group; or R³And R⁴Are connected together to form a bond, C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene or C_2-6A heteroalkenylene group;

R^5ais (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–C(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) or- (CR^5fR^5g)_n-a heteroaryl group;

R^5dand R^5eEach independently is (a) hydrogen or halo; (b) c _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5fAnd R^5gEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1c(ii) a or-S (O)₂NR^1bR^1c(ii) a Or (d) when one is present R^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_3–10Cycloalkyl or heterocyclyl;

R⁶is hydrogen, C_1-6Alkyl, -S-C_1-6Alkyl, -S (O) -C_1-6Alkyl or-SO₂–C_1-6An alkyl group;

m is 0 or 1; and is

n is 0, 1, 2, 3 or 4;

wherein R is¹、R²、R³、R⁴、R⁶、R^X、R^1a、R^1b、R^1c、R^1d、R^5a、R^5b、R^5c、R^5d、R^5e、R^5fAnd R^5gEach alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl in (a) is optionally substituted with one or more, and in one embodiment with one, two, three, four, or five substituents Q, wherein each substituent Q is independentlyIs selected from (a) oxo, cyano, halo and nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment with one, two, three or four substituents Q ^aSubstituted; and (c) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cand-S (O)₂NR^bR^cWherein each R is^a、R^b、R^cAnd R^dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is further optionally substituted with one or more, in one embodiment with one, two, three or four substituents Q^aSubstituted; or (iii) R^bAnd R^cTogether with the N atom to which they are attached form a heterocyclyl, which heterocyclyl is further optionally substituted by one or more, in one embodiment by one, two, three or four substituents Q^aSubstituted;

wherein each Q^aIndependently selected from (a) oxo, cyano, halo and nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl; and (c) -C (O) R^e、–C(O)OR^e、–C(O)NR^fR^g、–C(NR^e)NR^fR^g、–OR^e、–OC(O)R^e、–OC(O)OR^e、–OC(O)NR^fR^g、–OC(＝NR^e)NR^fR^g、–OS(O)R^e、–OS(O)₂R^e、–OS(O)NR^fR^g、–OS(O)₂NR^fR^g、–NR^fR^g、–NR^eC(O)R^h、–NR^eC(O)OR^h、–NR^eC(O)NR^fR^g、–NR^eC(＝NR^h)NR^fR^g、–NR^eS(O)R^h、–NR^eS(O)₂R^h、–NR^eS(O)NR^fR^g、–NR^eS(O)₂NR^fR^g、–SR^e、–S(O)R^e、–S(O)₂R^e、–S(O)NR^fR^gand-S (O)₂NR^fR^g(ii) a Wherein each R^e、R^f、R^gAnd R^hIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^fAnd R^gTogether with the N atom to which they are attached form a heterocyclyl; or

Wherein two substituents Q adjacent to each other optionally form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q ^aAnd (4) substituting.

In one embodiment of the compounds of formula (I),

x, Y and Z are each independently N or CR^XProvided that at least two of X, Y and Z are nitrogen atoms; wherein R is^XIs hydrogen or C_1-6An alkyl group;

R¹and R²Each independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a Wherein each R^1a、R^1b、R^1cAnd R^1dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^1bAnd R^1cTogether with the N atom to which they are attached form a heterocyclyl;

R³and R⁴Each independently isHydrogen or C_1-6An alkyl group; or R³And R⁴Are connected together to form a bond, C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene or C_2-6A heteroalkenylene group;

R^5ais (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) or- (CR ^5fR^5g)_n-a heteroaryl group;

R^5dand R^5eEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5fAnd R^5gEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1c(ii) a or-S (O)₂NR^1bR^1c(ii) a Or (d) when one is present R^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_3–10Cycloalkyl or heterocyclyl;

R⁶is hydrogen, C_1-6Alkyl and substituted benzeneS–C_1-6Alkyl, -S (O) -C_1-6Alkyl or-SO₂–C_1-6An alkyl group;

m is 0 or 1; and is

n is 0, 1, 2, 3 or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment with one, two, three, four, or five substituents Q as defined herein.

In another embodiment of the compounds of formula (I),

x, Y and Z are each independently N or CR^XProvided that at least two of X, Y and Z are nitrogen atoms; wherein R is ^XIs hydrogen or C_1-6An alkyl group;

R¹and R²Each independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a Wherein each R^1a、R^1b、R^1cAnd R^1dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^1bAnd R^1cTogether with the N atom to which they are attached form a heterocyclyl;

R³and R⁴Each independently is hydrogen or C_1-6An alkyl group; or R³And R⁴Are connected together to form a bond, C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene or C_2-6A heteroalkenylene group;

R^5ais (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) or- (CR^5fR^5g)_n-a heteroaryl group;

R^5dand R^5eEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R ^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5fAnd R^5gEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1c(ii) a or-S (O)₂NR^1bR^1c(ii) a Or (d) when one is present R^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_3–10Cycloalkyl or heterocyclyl;

R⁶is hydrogen, C_1-6Alkyl, -S-C_1-6Alkyl, -S (O) -C_1-6Alkyl or-SO₂–C_1-6An alkyl group;

m is 0 or 1; and is

n is 0, 1, 2, 3 or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment with one, two, three, four, or five substituents Q as defined herein.

In yet another embodiment of the compounds of formula (I),

x, Y and Z are each independently N or CR^XProvided that at least two of X, Y and Z are nitrogen atoms; wherein R is^XIs hydrogen or C_1-6An alkyl group;

R¹and R²Each independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C _6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a Wherein each R^1a、R^1b、R^1cAnd R^1dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^1bAnd R^1cTogether with the N atom to which they are attached form a heterocyclyl;

R³and R⁴Each independently is hydrogen or C_1-6An alkyl group; or R³And R⁴Are connected together to form a bond, C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene or C_2-6A heteroalkenylene group;

R^5ais (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) or- (CR^5fR^5g)_n-a heteroaryl group;

R^5dand R^5eEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5fAnd R^5gEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C _7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1c(ii) a or-S (O)₂NR^1bR^1c(ii) a Or (d) when one is present R^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_3–10Cycloalkyl or heterocyclyl;

R⁶is hydrogen, C_1-6Alkyl, -S-C_1-6Alkyl, -S (O) -C_1-6Alkyl or-SO₂–C_1-6An alkyl group;

m is 0 or 1; and is

n is 0, 1, 2, 3 or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment with one, two, three, four, or five substituents Q as defined herein.

In yet another embodiment of the compounds of formula (I),

x, Y and Z is N;

R¹and R²Each independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a Wherein each R^1a、R^1b、R^1cAnd R^1dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R ^1bAnd R^1cTogether with the N atom to which they are attached form a heterocyclyl;

R³and R⁴Each independently is hydrogen or C_1-6An alkyl group; or R³And R⁴Are connected together to form a bond, C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene or C_2-6A heteroalkenylene group;

R^5ais (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl or heteroaryl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) or- (CR^5fR^5g)_n-a heteroaryl group;

R^5dand R^5eEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5fAnd R^5gEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1c(ii) a or-S (O)₂NR^1bR^1c(ii) a Or (d) when one is present R^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_3–10Cycloalkyl or heterocyclyl;

R⁶Is hydrogen, C_1-6Alkyl, -S-C_1-6Alkyl, -S (O) -C_1-6Alkyl or-SO₂–C_1-6An alkyl group;

m is 0 or 1; and is

n is 0, 1, 2, 3 or 4;

wherein each alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more, in one embodiment with one, two, three, four, or five substituents Q as defined herein.

The synthesis of compounds of formula (I) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

Also provided herein are compounds of formula (IX):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^7a、R^7b、R^7c、R^7dand R^7eEach independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; or (c) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cor-S (O)₂NR^bR^c(ii) a Or

R^7a、R^7b、R^7c、R^7dAnd R^7eTwo of which are adjacent to each other form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R¹、R²、R³、R⁴、R⁶、R^1a、R^1b、R^1c、R^1d、R^5a、R^5b、R^5d、R^5eEach of X, Y and Z is as defined herein.

The synthesis of compounds of formula (IX) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In one embodiment, the compound of formula (IX) has the structure of formula (IXa):

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5d、R^5e、R^7a、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

The synthesis of compounds of formula (IXa) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In another embodiment, the compound of formula (IX) has the structure of formula (IXb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5d、R^5e、R^7a、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

The synthesis of compounds of formula (IXb) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C _6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, e.g. phenyl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is heteroaryl, e.g., 5-or 6-membered heteroaryl, optionally substituted with one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is heterocyclyl, e.g. 5-or 6-membered heterocyclyl, which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certain embodiments, R ^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb), R^7aIs C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R ^7aIs C_6-14Aryl radicals, e.g.Phenyl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs heteroaryl, e.g. 5-or 6-membered heteroaryl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs a heterocyclic group, e.g. a 5-or 6-membered heterocyclic group, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certain embodiments, R ^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piper inePyridin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb),

R¹is hydrogen OR-OR^1aWherein R is^1aIs C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R²Is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R^5aand R^5bEach independently hydrogen, halo, C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^5dand R^5eEach independently is C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CR^xProvided that at least two of X, Y and Z are N; wherein R is^xIs hydrogen or optionally substituted by one, two, three or four substituents Q^aSubstituted C_1-6An alkyl group.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is a taskC optionally substituted by one or more halo_1-6An alkyl group;

R^5aand R^5bIs hydrogen;

R^5dand R^5eEach independently is C_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais C_6-14Aryl, monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais phenyl, 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dAnd R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (IX), (IXa) or (IXb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

Also provided herein are compounds of formula (X):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5d、R^5e、R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

The synthesis of compounds of formula (X) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In one embodiment, the compound of formula (X) has the structure of formula (Xa):

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5d、R^5e、R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

The synthesis of compounds of formula (Xa) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In another embodiment, the compound of formula (X) has the structure of formula (Xb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5d、R^5e、R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

The synthesis of compounds of formula (Xb) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, e.g. phenyl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is heteroaryl, e.g., 5-or 6-membered heteroaryl, optionally substituted with one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is heterocyclyl, e.g. 5-or 6-membered heterocyclyl, which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; in some instancesIn the embodiment, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb), R^7aIs C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more substituents Q^aSubstituted; in certain embodiments, R^7aIs C_6-14Aryl, e.g. phenyl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs heteroaryl, e.g. 5-or 6-membered heteroaryl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs a heterocyclic group, e.g. a 5-or 6-membered heterocyclic group, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certain embodiments, R ^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyri-dinePyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb),

R¹is hydrogen OR-OR^1aWherein R is^1aIs C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R²is hydrogen;

R³And R⁴Is hydrogen;

R⁶is C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R^5aand R^5bEach independently hydrogen, halo, C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^5dand R^5eEach independently is C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one or more halo_1-6An alkyl group;

R^5aand R^5bIs hydrogen;

R^5dand R^5eEach is independentThe standing is C_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais C_6-14Aryl, monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais phenyl, 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In certain embodiments of the compounds of formula (X), (Xa), or (Xb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs hydrogen;

R^5dand R^5eIs methyl;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

Provided herein are compounds of formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^7a、R^7b、R^7c、R^7dand R^7eEach independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; or (c) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cor-S (O)₂NR^bR^c(ii) a Or

R^7a、R^7b、R^7c、R^7dAnd R^7eTwo of which are adjacent to each other form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R¹、R²、R³、R⁴、R⁶、R^1a、R^1b、R^1c、R^1d、R^5a、R^5b、R^5f、R^5gEach of X, Y and Z is as defined herein.

The synthesis of compounds of formula (XI) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In one embodiment, the compound of formula (XI) has the structure of formula (XIa):

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5f、R^5g、R^7a、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

The synthesis of compounds of formula (XIa) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In another embodiment, the compound of formula (XI) has the structure of formula (XIb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5f、R^5g、R^7a、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

The synthesis of compounds of formula (XIb) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In the formula (XI), (XIa) or (XIb)In certain embodiments of (A), R^5aAnd R^5bEach independently is (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a And R is¹、R²、R³、R⁴、R^5f、R^5g、R⁶、R^7a、R^7b、R^7c、R^7d、R^7e、X、Y、Z、R^1a、R^1b、R^1cAnd R^1dAs defined elsewhere herein.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, e.g. phenyl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R ^7a、R^7b、R^7c、R^7dAnd R^7eOne is heteroaryl, e.g., 5-or 6-membered heteroaryl, optionally substituted with one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is heterocyclyl, e.g. 5-or 6-membered heterocyclyl, which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one or more substituents Q^aSubstituted; in certain embodiments, R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certain embodiments, R ^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb), R^7aIs C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R ^7aIs C_6-14Aryl, e.g. phenyl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs heteroaryl, e.g. 5-or 6-membered heteroaryl, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs a heterocyclic group, e.g. a 5-or 6-membered heterocyclic group, optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; in certain embodiments, R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyPhenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and in certain embodiments, R ^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb),

R¹is hydrogen OR-OR^1aWherein R is^1aIs C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R²Is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R^5aand R^5bEach independently is C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^5fand R^5gEach independently is hydrogen, halo,C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group; or R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_1-10Cycloalkyl or heterocyclyl, each of which is optionally substituted with one, two, three, four or five substituents Q;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CR^xProvided that at least two of X, Y and Z are N; wherein R is^xIs hydrogen or optionally substituted by one, two, three or four substituents Q^aSubstituted C_1-6An alkyl group.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one or more halo_1-6An alkyl group;

R^5aand R^5bEach independently is C _1-6An alkyl group;

R^5fand R^5gEach independently is hydrogen or C_1-6An alkyl group; or R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_1-10A cycloalkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^5fand R^5gIs hydrogen; or R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group;

R^7ais C_6-14Aryl, monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^5fand R^5gIs hydrogen; or R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group;

R^7ais phenyl, 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^5fand R^5gIs hydrogen; or R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In certain embodiments of the compounds of formula (XI), (XIa), or (XIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^5fand R^5gIs hydrogen; or R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl group;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

Provided herein are compounds of formula (XVI):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

The synthesis of compounds of formula (XVI) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In one embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted C_6-14An aryl group; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R ^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyri-dinePyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl, or 4-methylpiperazin-1-yl.

In still another embodiment of the compounds of formula (XVI), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVI), R^7aIs C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In another embodiment of the compounds of formula (XVI), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted C_6-14An aryl group; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In-situ typeIn yet another embodiment of the compounds of (XVI), R^7aIs optionally substituted by one, two, three or four substituents Q ^aSubstituted heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In yet another embodiment of the compounds of formula (XVI), R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In yet another embodiment of the compounds of formula (XVI), R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R is ¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compound of formula (XVI),

R¹is hydrogen OR-OR^1aWherein R is^1aIs C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R^5aand R^5bEach independently is C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one or more substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVI),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one or more halo_1-6An alkyl group;

R^5aand R^5bEach independently is C_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVI),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^7ais C_6-14Aryl, monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVI),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^7ais phenyl, 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVI),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl or pyrimidylPyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one, two, three, four or five substituents Q; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVI),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bIs methyl;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment, the compound of formula (XVI) has the structure of formula (XVIa):

Or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

The synthesis of compounds of formula (XVIa) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, twoSingle, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted C_6-14An aryl group; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted 5-or 6-membered heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eIs optionally substituted by one, two, three or four substituents Q^aSubstituted heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、X、Y、Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In one embodiment of the compounds of formula (XVIa), R ^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted C_6-14An aryl group; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted heteroaryl; and R is ¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa), R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-ylPyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In one embodiment of the compounds of formula (XVIa), R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R is ¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIa),

R¹is hydrogen OR-OR^1aWherein R is^1aIs C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R^5aand R^5bEach independently hydrogen or C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compounds of formula (XVIa),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one or more halo_1-6An alkyl group;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compounds of formula (XVIa),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C _1-6An alkyl group;

R^7ais C_6-14Aryl, monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compounds of formula (XVIa),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compounds of formula (XVIa),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compounds of formula (XVIa),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen。

The synthesis of compounds of formula (XVIa) is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

In another embodiment, the compound of formula (XVI) has the structure of formula (XVIb):

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted C_6-14An aryl group; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of which is optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R ^7a、R^7b、R^7c、R^7dAnd R^7eOne is phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piper inePyridin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In one embodiment of the compounds of formula (XVIb), R^7a、R^7b、R^7c、R^7dAnd R^7eOne of them is phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5bX, Y, Z, and R^7a、R^7b、R^7c、R^7dAnd R^7eEach as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted with one, two, three, four or five substituents Q; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted C_6-14An aryl group; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs optionally one, two, three or four Substituent group Q^aSubstituted heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heteroaryl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs optionally substituted by one, two, three or four substituents Q^aSubstituted 5-or 6-membered heterocyclyl; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In-situ type(XVIb) one embodiment of the Compound, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and R is¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compounds of formula (XVIb), R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In one embodiment of the compounds of formula (XVIb), R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl, 2-methoxypyridin-4-yl, 1-methylpiperidin-4-yl, or 4-methylpiperazin-1-yl; and R is ¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^7b、R^7c、R^7d、R^7eEach of X, Y and Z is as defined herein.

In one embodiment of the compound of formula (XVIb),

R¹is hydrogen OR-OR^1aWherein R is^1aIs C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R^5aand R^5bEach independently hydrogen or C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one or more halo_1-6An alkyl group;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C _1-6An alkyl group;

R^7ais C_6-14Aryl, monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, imidazolyl, pyrazolyl,Pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted with one, two, three or four substituents Q^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compound of formula (XVIb),

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aSubstituted; and is

R^7b、R^7c、R^7dAnd R^7eIs hydrogen.

In one embodiment of the compounds of formula (XVI), (XVIa) or (XVIb), R^5aAnd R^5bEach independently is (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a And R is¹、R²、R³、R⁴、R⁶、R^7a、R^7b、R^7c、R^7d、R^7e、R^1a、R^1b、R^1cAnd R^1dAs defined elsewhere herein.

In one embodiment of any of the formulae provided herein,

R¹is hydrogen OR-OR^1aWherein R is^1aIs C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one, two, three, four or five substituents Q_1-6An alkyl group;

R^5aand R^5bEach independently hydrogen or C optionally substituted with one, two, three, four or five substituents Q_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CR^xProvided that at least two of X, Y and Z are N; wherein R is^xIs hydrogen or optionally substituted by one, two, three or four substituents Q^aSubstituted C_1-6An alkyl group.

In one embodiment of any of the formulae provided herein,

R¹Is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is C optionally substituted by one or more halo_1-6An alkyl group;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais C_6-14Aryl, monocyclic heteroaryl or monocyclic heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen；

R⁶Is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, 5-or 6-membered heteroaryl or 5-or 6-membered heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

R¹Is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In one embodiment of any of the formulae provided herein,

R¹is hydrogen or methoxy;

R²is hydrogen;

R³and R⁴Is hydrogen;

R⁶is difluoromethyl;

R^5aand R^5bEach independently is hydrogen or C_1-6An alkyl group;

R^7ais phenyl, imidazolyl, pyrazolyl, pyridyl or piperidylOr piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted;

R^7b、R^7c、R^7dand R^7eIs hydrogen; and is

X, Y and Z are each independently N or CH.

In the general formulae provided herein, for example in formulae (I), (IX), (X), (XI), (XVI), (Ia), (IXa), (Xa), (XIa), (XVIa), (Ib), (IXb), (Xb), (XIb), (XVIb), the radical or variable R¹、R²、R³、R⁴、R⁶、R^5a、R^5b、R^5c、R^5d、R^5e、R^5f、R^5g、R^7a、R^7b、R^7c、R^7d、R^7eM, n, X, Y and Z are further defined in the embodiments described herein. Embodiments provided herein are within the scope of the present disclosure for all combinations of such groups and/or variables.

In certain embodiments, R¹Is hydrogen. In certain embodiments, R¹Is cyano. In certain embodiments, R¹Is halo. In certain embodiments, R¹Is fluoro, chloro, bromo or iodo. In certain embodiments, R¹Is nitro. In certain embodiments, R¹Is C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R¹Is C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6An alkenyl group. In certain embodiments, R¹Is C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R¹Is C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, R¹Is optionally substituted with one, two, three, four or five substituents Q as described hereinC_6-14And (4) an aryl group. In certain embodiments, R¹Is C optionally substituted with one, two, three, four or five substituents Q as described herein _7-15An aralkyl group. In certain embodiments, R¹Is heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R¹Is heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R¹is-C (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-O-C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R¹Is methoxy, ethoxy, propoxy, isopropoxy or 3-dimethylaminopropoxy. In certain embodiments, R¹is-OC (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R ¹is-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In some embodiments of the present invention, the substrate is,R¹is-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-OS (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R¹is-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R¹is-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R¹is-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R ¹is-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R¹is-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-NR^1aS(O)₂NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-SR^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-S (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-S (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R¹is-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, R²Is hydrogen. In certain embodiments, R²Is cyano. In certain embodiments, R²Is halo. In certain embodiments, R²Is fluoro, chloro, bromo or iodo. In certain embodiments, R²Is nitro. In certain embodiments, R²Is C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R²Is C optionally substituted with one, two, three, four or five substituents Q as described herein _2-6An alkenyl group. In certain embodiments, R²Is C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R²Is C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, R²Is C optionally substituted with one, two, three, four or five substituents Q as described herein_3-7A cycloalkyl group. In certain embodiments, R²Is C optionally substituted with one, two, three, four or five substituents Q as described herein_6-14And (4) an aryl group. In certain embodiments, R²Is C optionally substituted with one, two, three, four or five substituents Q as described herein_7-15Aralkyl radicalAnd (4) a base. In certain embodiments, R²Is heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R²Is heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R²is-C (O) R^1aWherein R is ^1aAs defined herein. In certain embodiments, R²is-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R²is-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R¹is-O-C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R¹Is methoxy, ethoxy, propoxy, isopropoxy or 3-dimethylaminopropoxy. In certain embodiments, R²is-OC (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R²is-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R²is-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R ²is-OS (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R²is-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R²Is amino (-NH)₂). In certain embodiments, R²is-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R²is-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R²is-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R²is-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R²is-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R²is-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-NR^1aS(O)₂NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-SR ^1aWherein R is^1aAs defined herein. In certain embodiments, R²is-S (O)R^1aWherein R is^1aAs defined herein. In certain embodiments, R²is-S (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R²is-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R²is-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, R³Is hydrogen. In certain embodiments, R³Is C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R³Is hydrogen, methyl, ethyl or propyl (e.g., n-propyl, isopropyl or 2-isopropyl).

In certain embodiments, R⁴Is hydrogen. In certain embodiments, R⁴Is C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R⁴Is hydrogen, methyl, ethyl or propyl (e.g., n-propyl, isopropyl or 2-isopropyl).

In certain embodiments, R³And R⁴Joined together to form a bond. In certain embodiments, R³And R⁴Are linked together to form C optionally substituted with one, two, three, four or five substituents Q as described herein _1-6An alkylene group. In certain embodiments, R³And R⁴Linked together to form a methylene, ethylene or propylene group, each of which is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R³And R⁴Are linked together to form C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6A heteroalkylene group. In certain embodiments, R³And R⁴Are linked together to form a polymer optionally substituted with one,C substituted by two, three, four or five substituents Q as described herein_2-6An alkenylene group. In certain embodiments, R³And R⁴Are linked together to form C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6A heteroalkenylene group.

In certain embodiments, R⁶Is hydrogen. In certain embodiments, R⁶Is C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R⁶Is C optionally substituted by one or more, in one embodiment one, two or three halo_1-6An alkyl group. In certain embodiments, R ⁶Is C optionally substituted by one or more, in one embodiment one, two or three fluoro groups_1-6An alkyl group. In certain embodiments, R⁶Is methyl, fluoromethyl, difluoromethyl or trifluoromethyl. In certain embodiments, R⁶Is difluoromethyl. In certain embodiments, R⁶is-S-C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R⁶is-S (O) -C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R⁶is-SO₂–C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^5aIs hydrogen. In certain embodiments, R^5aIs not hydrogen. In certain embodiments, R^5aIs halo. In certain embodiments, R^5aIs fluoro, chloro, bromo or iodo. In certain embodiments, R^5aIs C optionally substituted with one, two, three, four or five substituents Q as described herein _1-6An alkyl group. In some embodimentsIn the scheme, R^5aIs methyl, ethyl, propyl, or butyl, each of which is optionally substituted with one, two, three, four, or five substituents Q as described herein. In certain embodiments, R^5aIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, R^5aIs methyl. In certain embodiments, R^5aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6An alkenyl group. In certain embodiments, R^5aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R^5aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, R^5aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_3-7A cycloalkyl group. In certain embodiments, R^5aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_6-14And (4) an aryl group. In certain embodiments, R ^5aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_7-15An aralkyl group. In certain embodiments, R^5aIs heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5aIs heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^5ais-C (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-C (O) OR^1aWherein R is^1aIs optionally substituted by one, two, three, four or five as described hereinC substituted by radicals Q_1-6An alkyl group. In certain embodiments, R^5ais-C (O) OCH₃. In certain embodiments, R^5ais-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-OC (O) R^1aWherein R is ^1aAs defined herein. In certain embodiments, R^5ais-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-OS (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5aIs amino (-NH)₂). In certain embodiments, R^5ais-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5ais-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5ais-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R ^5ais-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5ais-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5ais-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-NR^1aS(O)₂NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-SR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-S (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-S (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5ais-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5ais-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, R^5aIs (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl or heteroaryl, each of which is optionally substituted with one, two, three, four or five substituents Q; or (c) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c. In certain embodiments, R^5aIs (a) hydrogen or halo; or (b) C_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C _3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl or heteroaryl, each of which is optionally substituted with one, two, three, four or five substituents Q.

In certain embodiments, R^5bIs halo. In certain embodiments, R^5bIs fluoro, chloro, bromo or iodo. In certain embodiments, R^5bIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5bIs methyl, ethyl, propyl, or butyl, each of which is optionally substituted with one, two, three, four, or five substituents Q as described herein. In some implementationsIn the scheme, R^5bIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, R^5bIs methyl. In certain embodiments, R^5bIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6An alkenyl group. In certain embodiments, R^5bIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R^5bIs C optionally substituted with one, two, three, four or five substituents Q as described herein _3-10A cycloalkyl group. In certain embodiments, R^5bIs C optionally substituted with one, two, three, four or five substituents Q as described herein_3-7A cycloalkyl group. In certain embodiments, R^5bIs C optionally substituted with one, two, three, four or five substituents Q as described herein_6-14And (4) an aryl group. In certain embodiments, R^5bIs C optionally substituted with one, two, three, four or five substituents Q as described herein_7-15An aralkyl group. In certain embodiments, R^5bIs heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5bIs heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5bIs not a heterocyclic group.

In certain embodiments, R^5bis-C (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-C (O) OR^1aWherein R is^1aIs C optionally substituted with one, two, three, four or five substituents Q as described herein _1-6An alkyl group. In certain embodiments, R^5bis-C (O) OCH₃. In some instancesIn the embodiment, R^5bis-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-OC (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-OS (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R ^5bIs amino (-NH)₂). In certain embodiments, R^5bis-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5bis-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5bis-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R^5bis-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5bis-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5bis-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-NR^1aS(O)₂NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-SR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-S (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-S (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5bis-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5bis-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, R^5aAnd R^5bEach independently is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or tert-butyl, each of which is optionally substituted with one, two, three, four, or five substituents Q as described herein. In certain embodiments, R^5aAnd R^5bEach independentlyIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl, each of which is optionally substituted with one or more halo. In certain embodiments, R^5aAnd R^5bEach independently being methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, R^5aAnd R^5bEach is methyl.

In certain embodiments, R^5cIs C optionally substituted with one, two, three, four or five substituents Q as described herein_6-14And (4) an aryl group. In certain embodiments, R^5bIs C substituted in position 2 with a substituent Q as described herein_6-14And (4) an aryl group. In certain embodiments, R^5cIs phenyl or naphthyl, each of which is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cIs phenyl, naphthalen-1-yl or naphthalen-2-yl, each of which is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R ^5cIs phenyl, 4-chlorophenyl, 4-methoxyphenyl or naphthalen-2-yl. In certain embodiments, R^5cIs heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cIs monocyclic heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cIs a 5-or 6-membered heteroaryl group optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cIs a bicyclic heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) in which the C_6-14Aryl is optionally substituted with one, two, three, four or five substituents Q as described herein. In some instancesIn the embodiment, R^5cIs benzyl, 2-phenylethyl, 3-phenylpropyl or 4-phenylbutyl, wherein each phenyl moiety is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R ^5cIs benzyl, 2-phenylethyl, 3-phenylpropyl or 4-phenylbutyl. In certain embodiments, R^5cIs benzyl, fluorobenzyl, chlorobenzyl, bromobenzyl, cyanobenzyl, methylbenzyl or methoxybenzyl. In certain embodiments, R^5cIs (naphthalen-1-yl) methyl, (naphthalen-2-yl) methyl 2- (naphthalen-1-yl) ethyl, 2- (naphthalen-2-yl) ethyl, 3- (naphthalen-1-yl) propyl, 3- (naphthalen-2-yl) propyl, 4- (naphthalen-1-yl) butyl or 4- (naphthalen-2-yl) butyl, wherein each naphthyl moiety is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, n is 0 or 1. In one embodiment, n is 1. In one embodiment, n is 1, 2, 3 or 4. In certain embodiments, R^5cis-CH₂–(C_6-14Aryl) in which the C_6-14Aryl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cis-C (CH)₃)₂–(C_6-14Aryl) in which the C_6-14Aryl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cis-CH₂-phenyl or-CH₂-naphthyl, wherein the phenyl or naphthyl is each optionally substituted with one, two, three, four or five substituents Q as described herein, e.g. optionally with one or more F, Cl, Br, I, -CN, -CH ₃、–CF₃、–OCH₃or-OCF₃And (4) substituting. In certain embodiments, R^5cis-CH₂-phenyl, -CH₂-naphthalen-1-yl or-CH₂-naphthalen-2-yl, wherein the phenyl or naphthyl is each optionally substituted by one, two, three, four or five substituents Q as described herein, e.g. optionally by one or more of F, Cl, Br, I, -CN-CH₃、–CF₃、–OCH₃or-OCF₃And (4) substituting. In certain embodiments, R^5cis-CH₂-phenyl, -CH₂-naphthalen-1-yl or-CH₂-naphthalen-2-yl, wherein the phenyl or naphthyl is each optionally substituted by one or more of F, Cl, Br, I, -CN, -CH₃、–CF₃、–OCH₃、–OCF₃And (4) substituting. In other embodiments, R^5cis-CH₂-phenyl, -CH₂-naphthalen-1-yl or-CH₂-naphthalen-2-yl, wherein the phenyl or naphthyl is each optionally substituted with one or more of the following groups: F. cl, Br, I, -CN, -CH₃、–CF₃、–OCH₃、–OCF₃、–O–(C_1-4Alkylene) -N- (C)_1-4Alkyl radical)₂(e.g., -O-CH₂CH₂–N(CH₃)₂) -O-heterocyclyl (e.g, -O- (N-methylpiperidinyl) or-O-piperidinyl), -O-heteroaryl (e.g, -O-pyridinyl), -NH-heterocyclyl (e.g, -NH- (N-methylpiperidinyl), -NH- (N-methylpyrrolidinyl), -NH-piperidinyl or-NH-pyrrolidinyl), -NH-heteroaryl (e.g, -NH-pyridinyl), -NCH ₃-heterocyclyl (e.g., -NCH)₃- (N-methylpiperidinyl), -NCH₃- (N-methylpyrrolidinyl), -NCH₃-piperidinyl or-NCH₃-pyrrolidinyl), -NCH₃Heteroaryl (e.g., -NCH)₃-pyridyl), heterocyclyl (e.g. piperidyl, piperazinyl, N-methylpiperidinyl or N-methylpiperazinyl) or heteroaryl (e.g. pyridyl or imidazolyl). In certain embodiments, R^5cis-CH₂-phenyl, -C (CH)₃)₂-phenyl, -CH₂- (2-methylphenyl), -CH₂- (2-methoxylphenyl), -CH₂- (2-fluorophenyl), -CH₂- (2-chlorophenyl), -CH₂- (2-bromophenyl), -CH₂- (3-methylphenyl), -CH₂- (3-methoxylphenyl), -CH₂- (3-fluorophenyl), -CH₂- (3-chlorophenyl) -CH₂- (3-bromophenyl), -CH₂- (4-methylphenyl), -CH₂- (4-methoxylphenyl), -CH₂- (4-fluorophenyl), -CH₂- (4-chlorophenyl), -CH₂- (4-bromophenyl), -CH₂-naphthalen-1-yl or-CH₂-naphthalen-2-yl.

In certain embodiments, R^5cIs- (CR)^5fR^5g)–(C_6-14Aryl) in which the C_6-14Aryl is optionally substituted with one, two, three, four or five substituents Q as described herein, and wherein R is^5fAnd R^5gTogether with the carbon atom to which they are attached form a 3 to 6 membered cycloalkyl or heterocyclyl group. In one embodiment, R ^5cIs-cyclopropyl-phenyl. In one embodiment, R^5cIs-cyclobutyl-phenyl. In one embodiment, R^5cIs-cyclopentyl-phenyl. In one embodiment, R^5cIs-cyclohexyl-phenyl.

In certain embodiments, R^5cIs- (CR)^5fR^5g)_n-heteroaryl, wherein the heteroaryl is optionally substituted with one, two, three, four or five substituents Q as described herein, wherein n is as defined elsewhere herein. In certain embodiments, R^5cis-CH₂- (monocyclic heteroaryl), wherein the heteroaryl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cis-CH₂- (5-or 6-membered heteroaryl), wherein the heteroaryl is optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5cis-CH₂- (bicyclic heteroaryl), wherein the heteroaryl is optionally substituted with one, two, three, four or five substituents as described herein.

In certain embodiments, R^5dIs hydrogen. In certain embodiments, R^5dIs halo. In certain embodiments, R^5dIs fluoro, chloro, bromo or iodo. In some implementations In the scheme, R^5dIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5dIs methyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5dIs methyl. In certain embodiments, R^5dIs methyl, ethyl, propyl, or butyl, each of which is optionally substituted with one, two, three, four, or five substituents Q as described herein. In certain embodiments, R^5dIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, R^5dIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6An alkenyl group. In certain embodiments, R^5dIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R^5dIs C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, R^5dIs C optionally substituted with one, two, three, four or five substituents Q as described herein _6-14And (4) an aryl group. In certain embodiments, R^5dIs C optionally substituted with one, two, three, four or five substituents Q as described herein_7-15An aralkyl group. In certain embodiments, R^5dIs heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5dIs heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^5dis-C (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments，R^5dis-C (O) OR^1aWherein R is^1aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5dis-C (O) OCH₃. In certain embodiments, R^5dis-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R ^5dis-OC (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-OS (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dIs amino (-NH)₂). In certain embodiments, R^5dis-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5dis-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5dis-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is ^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R^5dis-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5dis-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5dis-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-NR^1aS(O)₂NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-SR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-S (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-S (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5dis-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5dis-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, R^5eIs hydrogen. In some implementationsIn the scheme, R^5eIs halo. In certain embodiments, R^5eIs fluoro, chloro, bromo or iodo. In certain embodiments, R^5eIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R ^5eIs methyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5eIs methyl. In certain embodiments, R^5eIs methyl, ethyl, propyl, or butyl, each of which is optionally substituted with one, two, three, four, or five substituents Q as described herein. In certain embodiments, R^5eIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, R^5eIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6An alkenyl group. In certain embodiments, R^5eIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R^5eIs C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, R^5eIs C optionally substituted with one, two, three, four or five substituents Q as described herein_6-14And (4) an aryl group. In certain embodiments, R^5eIs C optionally substituted with one, two, three, four or five substituents Q as described herein _7-15An aralkyl group. In certain embodiments, R^5eIs heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5eIs heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^5eis-C (O) R^1aWherein R is^1aAs defined herein.In certain embodiments, R^5eis-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-C (O) OR^1aWherein R is^1aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5eis-C (O) OCH₃. In certain embodiments, R^5eis-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-OC (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R ^5eis-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-OS (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined hereinAnd (5) defining. In certain embodiments, R^5eIs amino (-NH)₂). In certain embodiments, R^5eis-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5eis-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5eis-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R^5eis-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R ^5eis-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5eis-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-NR^1aS(O)₂NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-SR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-S (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-S (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5eis-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5eis-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, R^5fIs hydrogen. In certain embodiments, R^5fIs halo. In certain embodiments, R^5fIs fluoro, chloro, bromo or iodo. In certain embodiments, R^5fIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5fIs methyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R ^5fIs methyl. In certain embodiments, R^5fIs methyl, ethyl, propyl, or butyl, each of which is optionally substituted with one, two, three, four, or five substituents Q as described herein. In certain embodiments, R^5fIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, R^5fIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6An alkenyl group. In certain embodiments, R^5fIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R^5fIs C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, R^5fIs C optionally substituted with one, two, three, four or five substituents Q as described herein_6-14And (4) an aryl group. In certain embodiments, R^5fIs C optionally substituted with one, two, three, four or five substituents Q as described herein_7-15An aralkyl group. In certain embodiments, R^5fIs heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R ^5fIs heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^5fis-C (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-C (O) OR^1aWherein R is^1aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5fis-C (O) OCH₃. In certain embodiments, R^5fis-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fis-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fis-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-OC (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fis-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R ^5fis-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-OS (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fis-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein.In certain embodiments, R^5fis-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fIs amino (-NH)₂). In certain embodiments, R^5fis-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5fis-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5fis-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fis-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R^5fis-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5fis-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5fis-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fis-NR^1aS(O)₂NR^1bR^1cWherein R is ^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5fis-SR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-S (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-S (O)₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5fis-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as hereinAs defined. In certain embodiments, R^5fis-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, R^5gIs hydrogen. In certain embodiments, R^5gIs halo. In certain embodiments, R^5gIs fluoro, chloro, bromo or iodo. In certain embodiments, R^5gIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5gIs methyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, R^5gIs methyl. In certain embodiments, R^5gIs methyl, ethyl, propyl, or butyl, each of which is optionally substituted with one, two, three, four, or five substituents Q as described herein. In certain embodiments, R ^5gIs methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl or tert-butyl. In certain embodiments, R^5gIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6An alkenyl group. In certain embodiments, R^5gIs C optionally substituted with one, two, three, four or five substituents Q as described herein_2-6Alkynyl. In certain embodiments, R^5gIs C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, R^5gIs C optionally substituted with one, two, three, four or five substituents Q as described herein_6-14And (4) an aryl group. In certain embodiments, R^5gIs C optionally substituted with one, two, three, four or five substituents Q as described herein_7-15An aralkyl group. In certain embodiments, R^5gIs heteroaryl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments，R^5gIs heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^5gis-C (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-C (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-C (O) OR^1aWherein R is^1aIs C optionally substituted with one, two, three, four or five substituents Q as described herein_1-6An alkyl group. In certain embodiments, R^5gis-C (O) OCH₃. In certain embodiments, R^5gis-C (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-C (NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-OC (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-OC (O) OR^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-OC (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-OC (═ NR)^1a)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-OS (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-OS (O) ₂R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-OS (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In some embodiments of the present invention, the substrate is,R^5gis-OS (O)₂NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gIs amino (-NH)₂). In certain embodiments, R^5gis-NR^1aC(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5gis-NR^1aC(O)OR^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5gis-NR^1aC(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-NR^1aC(＝NR^1d)NR^1bR^1cWherein R is^1a、R^1b、R^1cAnd R^1dEach as defined herein. In certain embodiments, R^5gis-NR^1aS(O)R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5gis-NR^1aS(O)₂R^1dWherein R is^1aAnd R^1dEach as defined herein. In certain embodiments, R^5gis-NR^1aS(O)NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-NR^1aS(O)₂NR^1bR^1cWherein R is^1a、R^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-SR^1aWherein R is ^1aAs defined herein. In certain embodiments, R^5gis-S (O) R^1aWherein R is^1aAs defined herein. In certain embodiments, R^5gis-S (O)₂R^1aWherein R is^1aAs defined herein. In thatIn certain embodiments, R^5gis-S (O) NR^1bR^1cWherein R is^1bAnd R^1cEach as defined herein. In certain embodiments, R^5gis-S (O)₂NR^1bR^1c(ii) a Wherein R is^1bAnd R^1cEach as defined herein.

In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C optionally substituted with one, two, three, four or five substituents Q as described herein_3-10A cycloalkyl group. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C optionally substituted with one, two, three, four or five substituents Q as described herein_3-7A cycloalkyl group. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclopropyl group optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present ^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclobutyl group, optionally substituted by one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclopentyl group optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclohexyl group optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cycloheptyl group optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present ^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a cyclopropyl group.

In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a 3-membered heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a 4-membered heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form a 5-membered heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein. In certain embodiments, when one R is present ^5fAnd one present R^5gIs connected toWhen they are the same carbon atom, R is^5fAnd R^5gTogether with the carbon atom to which they are attached form a 6 membered heterocyclyl optionally substituted with one, two, three, four or five substituents Q as described herein.

In certain embodiments, R^7aIs hydrogen. In certain embodiments, R^7aIs cyano. In certain embodiments, R^7aIs halo. In certain embodiments, R^7aIs fluoro, chloro, bromo or iodo. In certain embodiments, R^7aIs nitro. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_1-6An alkyl group. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_2-6An alkenyl group. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_2-6Alkynyl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-7A cycloalkyl group. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein ^aSubstituted C_3-10A cycloalkyl group. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted phenyl. In certain embodiments, R^7aIs phenyl optionally substituted with one or more substituents each independently selected from fluoro, chloro, bromo, methyl and methoxy. In certain embodiments, R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methoxyphenyl,4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_7-15An aralkyl group. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted heteroaryl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein ^aSubstituted monocyclic heteroaryl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted 5-membered heteroaryl. In certain embodiments, R^7aIs imidazolyl or pyrazolyl optionally substituted with one, two, three or four substituents Q as described herein^aAnd (4) substituting. In certain embodiments, R^7aIs imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl or 2-methylpyrazol-3-yl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted 6-membered heteroaryl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted pyridyl. In certain embodiments, R^7aIs pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-methylpyridin-4-yl or 2-methoxypyridin-4-yl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted heterocyclyl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein ^aSubstituted monocyclic heterocyclyl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted 5-membered heterocyclyl. In certain embodiments, R^7aIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted 6A heterocyclic radical. In certain embodiments, R^7aIs piperidinyl or piperazinyl, optionally substituted with one, two, three or four substituents Q as described herein^aAnd (4) substituting. In certain embodiments, R^7aIs 1-methylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments, R^7ais-C (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-C (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-C (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-C (NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-OR^aWherein R is^aAs defined herein. In certain embodiments, R^ais-O-C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three or four substituents Q as described herein ^aAnd (4) substituting. In certain embodiments, R^aIs methoxy, ethoxy, propoxy, isopropoxy or 3-dimethylaminopropoxy. In certain embodiments, R^7ais-OC (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-OC (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-OC (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-OC (═ NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-OS (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-OS (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-OS (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-OS (O)₂NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7aIs amino (-NH)₂). In certain embodiments, R^7ais-NR^aC(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7ais-NR^aC(O)OR^dWherein R is^aAnd R ^dEach as defined herein. In certain embodiments, R^7ais-NR^aC(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-NR^aC(＝NR^d)NR^bR^cWherein R is^a、R^b、R^cAnd R^dEach as defined herein. In certain embodiments, R^7ais-NR^aS(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7ais-NR^aS(O)₂R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7ais-NR^aS(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-NR^aS(O)₂NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-SR^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-S (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-S (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7ais-S (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7ais-S (O)₂NR^bR^c(ii) a Wherein R is^bAnd R^cEach as defined herein.

In certain embodiments, R^7aIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q ^aAnd (4) substituting. In certain embodiments, R^7aIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In certain embodiments, R^7bIs hydrogen. In certain embodiments, R^7bIs cyano. In certain embodiments, R^7bIs halo. In certain embodiments, R ^7bIs fluoro, chloro, bromo or iodo. In certain embodiments, R^7bIs nitro. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_1-6An alkyl group. In some embodiments of the present invention, the substrate is,R^7bis optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_2-6An alkenyl group. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_2-6Alkynyl. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-10A cycloalkyl group. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-7A cycloalkyl group. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_7-15An aralkyl group. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein ^aSubstituted heteroaryl. In certain embodiments, R^7bIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted heterocyclyl.

In certain embodiments, R^7bis-C (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-C (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-C (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-C (NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-OR^aWherein R is^aAs defined herein. In certain embodiments, R^ais-O-C_1-6Alkyl, wherein the alkyl is optionallyBy one, two, three or four substituents Q as described herein^aAnd (4) substituting. In certain embodiments, R^aIs methoxy, ethoxy, propoxy, isopropoxy or 3-dimethylaminopropoxy. In certain embodiments, R^7bis-OC (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-OC (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-OC (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R ^7bis-OC (═ NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-OS (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-OS (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-OS (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-OS (O)₂NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7bIs amino (-NH)₂). In certain embodiments, R^7bis-NR^aC(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7bis-NR^aC(O)OR^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7bis-NR^aC(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-NR^aC(＝NR^d)NR^bR^cWherein R is^a、R^b、R^cAnd R^dEach as defined herein. In certain embodiments, R^7bis-NR^aS(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7bis-NR^aS(O)₂R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7bis-NR ^aS(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-NR^aS(O)₂NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-SR^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-S (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-S (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7bis-S (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7bis-S (O)₂NR^bR^c(ii) a Wherein R is^bAnd R^cEach as defined herein.

In certain embodiments, R^7bIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7bIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl 3-morpholin-4-ylmethyl-phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, imidazol-1-yl, pyridin-4-yl, and the like, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments, R^7cIs hydrogen. In certain embodiments, R^7cIs cyano. In certain embodiments, R^7cIs halo. In certain embodiments, R^7cIs fluoro, chloro, bromo or iodo. In certain embodiments, R^7cIs nitro. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_1-6An alkyl group. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_2-6An alkenyl group. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein ^aSubstituted C_2-6Alkynyl. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-10A cycloalkyl group. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-7A cycloalkyl group. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_7-15An aralkyl group. In certain embodiments, R^7cIs optionally one or twoOne, three or four substituents Q as described herein^aSubstituted heteroaryl. In certain embodiments, R^7cIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted heterocyclyl.

In certain embodiments, R^7cis-C (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-C (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-C (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R ^7cis-C (NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7cis-OR^aWherein R is^aAs defined herein. In certain embodiments, R^ais-O-C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three or four substituents Q as described herein^aAnd (4) substituting. In certain embodiments, R^aIs methoxy, ethoxy, propoxy, isopropoxy or 3-dimethylaminopropoxy. In certain embodiments, R^7cis-OC (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-OC (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-OC (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7cis-OC (═ NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7cis-OS (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-OS (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-OS (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7cis-OS (O)₂NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R ^7cis-NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7cIs amino (-NH)₂). In certain embodiments, R^7cis-NR^aC(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7cis-NR^aC(O)OR^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7cis-NR^aC(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7cis-NR^aC(＝NR^d)NR^bR^cWherein R is^a、R^b、R^cAnd R^dEach as defined herein. In certain embodiments, R^7cis-NR^aS(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7cis-NR^aS(O)₂R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7cis-NR^aS(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7cis-NR^aS(O)₂NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7cis-SR^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-S (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-S (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7cis-S (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R ^7cis-S (O)₂NR^bR^c(ii) a Wherein R is^bAnd R^cEach as defined herein.

In certain embodiments, R^7cIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7cIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In certain embodiments, R^7dIs hydrogen. In certain embodiments, R^7dIs cyano. In certain embodiments, R^7dIs halo. In certain embodiments, R^7dIs fluoro, chloro, bromo or iodo. In certain embodiments, R^7dIs nitro. In certain embodiments, R^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_1-6An alkyl group. In certain embodiments, R^7dIs optionally substituted by one,Two, three or four substituents Q as described herein^aSubstituted C_2-6An alkenyl group. In certain embodiments, R^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_2-6Alkynyl. In certain embodiments, R^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-10A cycloalkyl group. In certain embodiments, R^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-7A cycloalkyl group. In certain embodiments, R^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R ^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_7-15An aralkyl group. In certain embodiments, R^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted heteroaryl. In certain embodiments, R^7dIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted heterocyclyl.

In certain embodiments, R^7dis-C (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-C (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-C (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-C (NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-OR^aWherein R is^aAs defined herein. In certain embodiments, R^ais-O-C_1-6Alkyl, wherein the alkyl is optionally substituted by one, two, three or four such asSubstituent Q as described herein^aAnd (4) substituting. In certain embodiments, R^aIs methoxy, ethoxy, propoxy, isopropoxy or 3-dimethylaminopropoxy. In certain embodiments, R ^7dis-OC (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-OC (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-OC (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-OC (═ NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-OS (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-OS (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-OS (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-OS (O)₂NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7dIs amino (-NH)₂). In certain embodiments, R^7dis-NR^aC(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7dis-NR^aC(O)OR^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7dis-NR^aC(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-NR^aC(＝NR^d)NR^bR^cWherein R is ^a、R^b、R^cAnd R^dEach as defined herein. In certain embodiments, R^7dis-NR^aS(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7dis-NR^aS(O)₂R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7dis-NR^aS(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-NR^aS(O)₂NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-SR^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-S (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-S (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7dis-S (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7dis-S (O)₂NR^bR^c(ii) a Wherein R is^bAnd R^cEach as defined herein.

In certain embodiments, R^7dIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7dIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazole -1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, p-butyl-methyl-benzyl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl.

In certain embodiments, R^7eIs hydrogen. In certain embodiments, R^7eIs cyano. In certain embodiments, R^7eIs halo. In certain embodiments, R^7eIs fluoro, chloro, bromo or iodo. In certain embodiments, R^7eIs nitro. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_1-6An alkyl group. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_2-6An alkenyl group. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein ^aSubstituted C_2-6Alkynyl. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-10A cycloalkyl group. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_3-7A cycloalkyl group. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted C_7-15An aralkyl group. In certain embodiments, R^7eIs optionally one, two, three or four as described hereinSubstituent group Q^aSubstituted heteroaryl. In certain embodiments, R^7eIs optionally substituted by one, two, three or four substituents Q as described herein^aSubstituted heterocyclyl.

In certain embodiments, R^7eis-C (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-C (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-C (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R ^7eis-C (NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7eis-OR^aWherein R is^aAs defined herein. In certain embodiments, R^ais-O-C_1-6Alkyl, wherein the alkyl is optionally substituted with one, two, three or four substituents Q as described herein^aAnd (4) substituting. In certain embodiments, R^aIs methoxy, ethoxy, propoxy, isopropoxy or 3-dimethylaminopropoxy. In certain embodiments, R^7eis-OC (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-OC (O) OR^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-OC (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7eis-OC (═ NR)^a)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7eis-OS (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-OS (O)₂R^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-OS (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7eis-OS (O)₂NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R ^7eis-NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R^7eIs amino (-NH)₂). In certain embodiments, R^7eis-NR^aC(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7eis-NR^aC(O)OR^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7eis-NR^aC(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7eis-NR^aC(＝NR^d)NR^bR^cWherein R is^a、R^b、R^cAnd R^dEach as defined herein. In certain embodiments, R^7eis-NR^aS(O)R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7eis-NR^aS(O)₂R^dWherein R is^aAnd R^dEach as defined herein. In certain embodiments, R^7eis-NR^aS(O)NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7eis-NR^aS(O)₂NR^bR^cWherein R is^a、R^bAnd R^cEach as defined herein. In certain embodiments, R^7eis-SR^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-S (O) R^aWherein R is^aAs defined herein. In certain embodiments, R^7eis-S (O)₂R^aWherein R is^aAs used hereinAnd (4) defining. In certain embodiments, R^7eis-S (O) NR^bR^cWherein R is^bAnd R^cEach as defined herein. In certain embodiments, R ^7eis-S (O)₂NR^bR^c(ii) a Wherein R is^bAnd R^cEach as defined herein.

In certain embodiments, R^7eIs phenyl, imidazolyl, pyrazolyl, pyridyl, pyrimidinyl, pyrrolidinyl, piperidinyl or piperazinyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7eIs phenyl, 2-fluorophenyl, 2-chlorophenyl, 2-bromophenyl, 2-methylphenyl, 2- (3-dimethylaminopropyl) phenyl, 2-methoxyphenyl, 3-fluorophenyl, 3-chlorophenyl, 3-methylphenyl, 3-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-bromophenyl, 4-methoxyphenyl, 2, 4-difluorophenyl, 2, 6-difluorophenyl, 4-fluoro-3-methoxyphenyl, 4-methoxyphenyl, 3-morpholin-4-ylmethyl phenyl, imidazol-1-yl, pyrazol-4-yl, 1-methyl-pyrazol-4-yl, methyl-benzyl, 2-methylpyrazol-3-yl, pyridin-2-yl, pyridin-3-yl, pyridin-4-yl, 2-fluoropyridin-3-yl, 2-methylpyridin-4-yl, 2- (4-methylpiperazin-1-yl) pyridin-4-yl, 2-methoxypyridin-4-yl, pyrimidin-5-yl, pyrrolidin-3-yl, 1-methylpyrrolidin-3-yl, piperidin-4-yl, 1-methylpiperidin-4-yl, 1-ethylpiperidin-4-yl, 1-isopropylpiperidin-4-yl, 1-acetylpiperidin-4-yl, 1-methylsulfonylpiperidin-4-yl or 4-methylpiperazin-1-yl -a radical.

In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted C_3-10A cycloalkenyl group. In certain embodiments, R^7aAnd R^7bWith carbon atoms to which they are attachedTogether form a group optionally substituted by one, two, three or four substituents Q^aSubstituted cyclohexenyl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted phenyl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted heteroaryl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents ^aSubstituted monocyclic heteroaryl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heteroaryl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heteroaryl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted heterocyclyl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted monocyclic heterocyclyl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heterocyclyl. In certain embodiments, R^7aAnd R^7bTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heterocyclic group.

In certain embodiments, R ^7bAnd R^7cTogether with the carbon atom to which they are attached form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted C_3-10A cycloalkenyl group. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted cyclohexenyl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted phenyl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted heteroaryl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents ^aSubstituted monocyclic heteroaryl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heteroaryl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heteroaryl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form an optionally substituted one, two, three orFour substituents Q^aSubstituted heterocyclyl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted monocyclic heterocyclyl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heterocyclyl. In certain embodiments, R^7bAnd R^7cTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heterocyclic group.

In certain embodiments, R ^7cAnd R^7dTogether with the carbon atom to which they are attached form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted C_3-10A cycloalkenyl group. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted cyclohexenyl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted phenyl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted heteroaryl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form an optionally mono Single, two, three or four substituents Q^aSubstituted monocyclic heteroaryl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heteroaryl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heteroaryl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted heterocyclyl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted monocyclic heterocyclyl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heterocyclyl. In certain embodiments, R^7cAnd R^7dTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heterocyclic group.

In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted C_3-10A cycloalkenyl group. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted cyclohexenyl. In certain embodiments, R^7dAnd R^7eTo which they are connectedThe carbon atoms together forming a Q optionally substituted by one, two, three or four substituents^aSubstituted C_6-14And (4) an aryl group. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted phenyl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted heteroaryl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents ^aSubstituted monocyclic heteroaryl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heteroaryl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heteroaryl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted heterocyclyl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted monocyclic heterocyclyl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted 5-or 6-membered heterocyclyl. In certain embodiments, R^7dAnd R^7eTogether with the carbon atom to which they are attached form a group Q optionally substituted by one, two, three or four substituents^aSubstituted bicyclic heterocyclic group.

In certain embodiments, m is 0. In certain embodiments, m is 1.

In certain embodiments, n is 0. In certain embodiments, n is 1. In certain embodiments, n is 2. In certain embodiments, n is 3. In certain embodiments, n is 4. In certain embodiments, n is 0, 1, or 2. In certain embodiments, n is 0, 1, 2, or 3. In certain embodiments, n is 1, 2, or 3. In certain embodiments, n is 1 or 2.

In certain embodiments, m is 0 and n is 0, 1, 2, or 3. In certain embodiments, m is 0 and n is 0, 1 or 2. In certain embodiments, m is 0 and n is 0 or 1. In certain embodiments, m is 0 and n is 0. In certain embodiments, m is 0 and n is 1. In certain embodiments, m is 1 and n is 0, 1, 2, or 3. In certain embodiments, m is 1 and n is 0, 1 or 2. In certain embodiments, m is 1 and n is 0 or 1. In certain embodiments, m is 1 and n is 0. In certain embodiments, m is 1 and n is 1.

In particular embodiments, m is 0, n is 1, and R^5aAnd R^5bEach is methyl.

In certain embodiments, X is N. In certain embodiments, X is CR^xWherein R is^xAs defined herein. In certain embodiments, X is CH.

In certain embodiments, Y is N. In certain embodiments, Y is CR^xWherein R is^xAs defined herein. In certain embodiments, Y is CH.

In certain embodiments, Z is N. In certain embodiments, Z is CR^xWherein R is^xAs defined herein. In certain embodiments, Z is CH.

In certain embodiments, X, Y and Z are N. In certain embodiments, X and Y are N, and Z is CH. In certain embodiments, X and Z are N, and Y is CH. In certain embodiments, Y and Z are N, and X is CH.

In certain embodiments, the compound provided herein is not 4- (2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl) -6-morpholino-N- (2-phenyl-2- (pyrrolidin-1-yl) ethyl) -1,3, 5-triazin-2-amine. In certain embodiments, the compound provided herein is not 6- (2- (difluoromethyl) -1H-benzo [ d ] imidazol-1-yl) -N- (1- (4- ((R) -3- (methoxymethyl) morpholino) phenyl) ethyl) -2-morpholinopyrimidin-4-amine.

In certain embodiments, when X, Y and Z are N, and R is^5aWhen it is hydrogen, R^5bIs not a heterocyclic group. In certain embodiments, when X, Y and Z are N, and R is^5aWhen it is hydrogen, R^5bIs not a 5-membered heterocyclic group. In certain embodiments, when X, Y and Z are N, and R is ^5aWhen it is hydrogen, R^5bIs not pyrrolidinyl. In certain embodiments, when X, Y and Z are N, and R is^5aWhen it is hydrogen, R^5bIs not pyrrolidin-1-yl.

In certain embodiments, when X and Z are N, Y is CH, and R^5aWhen it is hydrogen, R^5bIs a morpholino substituted phenyl group. In certain embodiments, when X and Z are N, Y is CH, and R^5aWhen it is hydrogen, R^5bIs not 4- ((R) -3- (methoxymethyl) morpholino) phenyl.

In one embodiment, provided herein is a compound selected from the group consisting of:

in one embodiment, the PI3K inhibitor is compound I, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound II, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound III, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound IV, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound V, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound VI, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound VII, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound VIII, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound IX, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound X, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound XI, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound XII, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound XIII, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound XIV, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound XV, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In one embodiment, the PI3K inhibitor is compound XVI, an isotopic variant, a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

A second medicament

Some embodiments provided herein describe pharmaceutical compositions comprising or methods of using a combination of a PI3K inhibitor and a BTK inhibitor described herein.

Any suitable BTK inhibitor can be used in combination with the PI3K inhibitors described herein. In some embodiments, the BTK inhibitor is ibrutinib, BGB-3111, CC-292, ACP 196, CNX-774, CGI1746, LFM-A13, CNX-774, ONO-4059, RN486CPI-0610, DUAL946, GSK525762, I-BET151, JQ1, OTX015, PFI-1, RVX-208, RVX2135, TEN-010, or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is ibrutinib, or a pharmaceutically acceptable salt thereof, or BGB-3111, or a pharmaceutically acceptable salt thereof. In another embodiment, the BTK inhibitor is ibrutinib, or a pharmaceutically acceptable salt thereof. In yet another embodiment, the BTK inhibitor is BGB-3111, or a pharmaceutically acceptable salt thereof.

Application method

In certain embodiments, provided herein are methods of treating or preventing a disease comprising administering an effective amount of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and an effective amount of a BTK inhibitor. In some embodiments, the BTK inhibitor is ibrutinib or BGB-3111, or a pharmaceutically acceptable salt thereof. In some embodiments, the BTK inhibitor is BGB-3111 or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is compound I or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound II or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound III or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound IV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound V or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VI or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VIII or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound IX or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound X or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XI or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XIII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound XIV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound XV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XVI or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In one embodiment, provided herein is a method of treating or preventing cancer comprising administering to a subject in need thereof a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and an effective amount of a BTK inhibitor. In one embodiment, the BTK inhibitor is ibrutinib or BGB-3111, or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of formula (I) is compound I. In some embodiments, the compound of formula (I) is compound II. In some embodiments, the compound of formula (I) is compound III. In some embodiments, the compound of formula (I) is compound IV. In some embodiments, the compound of formula (I) is compound V. In some embodiments, the compound of formula (I) is compound VI. In some embodiments, the compound of formula (I) is compound VII. In some embodiments, the compound of formula (I) is compound VIII. In some embodiments, the compound of formula (I) is compound IX. In some embodiments, the compound of formula (I) is compound X. In some embodiments, the compound of formula (I) is compound XI. In some embodiments, the compound of formula (I) is compound XII. In some embodiments, the compound of formula (I) is compound XIII. In some embodiments, the compound of formula (I) is compound XIV. In some embodiments, the compound of formula (I) is compound XV. In some embodiments, the compound of formula (I) is compound XVI.

In certain embodiments, the proliferative disease is cancer. In certain embodiments, the proliferative disease is a hematological cancer or a malignancy.

In certain embodiments, the proliferative disease is breast cancer, skin cancer, prostate cancer, cervical cancer, uterine cancer, ovarian cancer, testicular cancer, bladder cancer, lung cancer, liver cancer, laryngeal cancer, oral cancer, colon and gastrointestinal cancer (e.g., esophageal cancer, gastric cancer, pancreatic cancer), brain cancer, thyroid cancer, blood cancer, and cancer of the lymphatic system.

In certain embodiments, cancers that can be treated using the methods provided herein include, but are not limited to: (1) leukemias, including but not limited to acute leukemia, acute lymphocytic leukemia, acute myelocytic leukemia, such as medulloblastoma, promyelocytic, myelomonocytic, monocytic leukemia, erythroleukemia, and myelodysplastic syndrome or symptoms thereof (such as anemia, thrombocytopenia, neutropenia, bilinear cytopenia (bicytopenia) or pancytopenia), Refractory Anemia (RA), RA with annular sideroblasts (RARS), RA with blast (RAEB), transformed RAEB (RAEB-T), leukemic pre-and chronic myelomonocytic leukemia (CMML), (2) chronic leukemias, including but not limited to chronic myelocytic (granulocytic) leukemia, chronic lymphocytic leukemia, and hairy cell leukemia; (3) polycythemia vera; (4) lymphomas, including but not limited to hodgkin's disease and non-hodgkin's disease; (5) multiple myeloma, including but not limited to smoldering multiple myeloma, non-secretory myeloma, sclerosteous myeloma, plasma cell leukemia, solitary plasmacytoma, and extramedullary plasmacytoma; (6) waldenstrom's macroglobulinemia; (7) monoclonal gammopathy of undetermined significance; (8) benign monoclonal gammopathy; (9) heavy chain disease; (10) bone and connective tissue sarcomas including, but not limited to, skeletal sarcoma, osteosarcoma, chondrosarcoma, ewing's sarcoma, malignant giant cell tumor, bone fibrosarcoma, chordoma, periosteal sarcoma, soft tissue sarcoma, angiosarcoma (angioendothelioma), fibrosarcoma, kaposi's sarcoma, leiomyosarcoma, liposarcoma, lymphangiosarcoma, metastatic cancer, schwannoma, rhabdomyosarcoma, and synovial sarcoma; (11) brain tumors, including but not limited to glioma, astrocytoma, brain stem glioma, ependymoma, oligodendroglioma, non-glioma, acoustic neuroma, craniopharyngioma, medulloblastoma, meningioma, pinealoblastoma, and primary brain lymphoma; (12) breast cancers including, but not limited to, adenocarcinoma, lobular (small cell) carcinoma, intraductal carcinoma, medullary breast cancer, mucinous breast cancer, tubular breast cancer, papillary breast cancer, primary cancer, paget's disease, and inflammatory breast cancer; (13) adrenal cancer including but not limited to pheochromocytoma and adrenocortical carcinoma; (14) thyroid cancer including, but not limited to papillary or follicular thyroid cancer, medullary thyroid cancer, and undifferentiated thyroid cancer; (15) pancreatic cancer including but not limited to insulinoma, gastrinoma, glucagonoma, vipoma, somatostatin-secreting tumors, and carcinoid or islet cell tumor; (16) pituitary cancers including but not limited to cushing's disease, prolactin-secreting tumors, acromegaly, and diabetes insipidus; (17) eye cancers including, but not limited to, ocular melanoma, such as iris melanoma, choroidal melanoma, ciliary body melanoma, and retinoblastoma; (18) vaginal cancers including but not limited to squamous cell carcinoma, adenocarcinoma, and melanoma; (19) vulvar cancers including, but not limited to, squamous cell carcinoma, melanoma, adenocarcinoma, basal cell carcinoma, sarcoma, and paget's disease; (20) cervical cancer including but not limited to squamous cell carcinoma and adenocarcinoma; (21) uterine cancers including but not limited to endometrial cancer and uterine sarcoma; (22) ovarian cancers including, but not limited to, ovarian epithelial cancers, borderline tumors, germ cell tumors, and stromal tumors; (23) esophageal cancer including, but not limited to, squamous cell carcinoma, adenocarcinoma, adenoid cystic carcinoma, mucoepidermoid carcinoma, adenosquamous carcinoma, sarcoma, melanoma, plasmacytoma, verrucous carcinoma, and oat cell (small cell) carcinoma; (24) gastric cancer, including but not limited to adenocarcinoma, mycosis (polypoid), ulceration, superficial spreading, diffuse spreading, malignant lymphoma, liposarcoma, fibrosarcoma, and carcinosarcoma; (25) colon cancer; (26) rectal cancer; (27) liver cancer, including but not limited to hepatocellular carcinoma and hepatoblastoma; (28) gallbladder cancer, including but not limited to adenocarcinoma; (29) cholangiocarcinoma, including but not limited to papillary, nodular, and diffuse; (30) lung cancer including, but not limited to, non-small cell lung cancer, squamous cell carcinoma (epidermoid carcinoma), adenocarcinoma, large cell carcinoma, and small cell lung cancer; (31) testicular cancer including, but not limited to, germ cell tumor, seminoma, anaplastic, classical (typicality), seminoma, non-seminoma, embryonal carcinoma, teratoma carcinoma, and choriocarcinoma (yolk sac tumor); (32) prostate cancer including but not limited to adenocarcinoma, leiomyosarcoma, and rhabdomyosarcoma; (33) penile cancer (penile cancer); (34) oral cancer, including but not limited to squamous cell carcinoma; (35) basal cell carcinoma; (36) salivary gland cancers including but not limited to adenocarcinoma, mucoepidermoid carcinoma, and adenoid cystic carcinoma; (37) pharyngeal cancer, including but not limited to squamous cell carcinoma and verrucous; (38) skin cancers including but not limited to basal cell carcinoma, squamous cell carcinoma and melanoma, superficial diffuse melanoma, nodular melanoma, lentigo maligna melanoma, and acrolentigo melanoma; (39) kidney cancers, including but not limited to renal cell carcinoma, adenocarcinoma, suprarenal adenoid tumor, fibrosarcoma, and transitional cell carcinoma (renal pelvis and/or ureter); (40) wilms' tumor; (41) bladder cancer including, but not limited to, transitional cell carcinoma, squamous cell carcinoma, adenocarcinoma, and carcinosarcoma; and other cancers, including but not limited to myxosarcoma, osteogenic sarcoma, endotheliosarcoma, lymphangioendotheliosarcoma, mesothelioma, synovioma, hemangioblastoma, epithelial carcinoma, cystadenocarcinoma, bronchogenic carcinoma, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, and papillary adenocarcinoma (see, fisherman et al, 1985, Medicine, 2 nd edition, j.b. lippincott co., philidelphia and Murphy et al, 1997, informational Decisions: The complex Book of Cancer Diagnosis, Treatment, and Recovery, Viking Penguin, Penguin Books u.s.s.a., inc., United States of America).

In certain embodiments, provided herein are methods of treating a hematologic malignancy in a patient with an effective amount of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, in combination with an effective amount of a BTK inhibitor (e.g., BGB-3111). In certain embodiments, the hematological malignancy is a leukemia, lymphoma, myeloma, non-hodgkin's lymphoma, T cell malignancy, or B cell malignancy. In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia, follicular lymphoma, diffuse large B-cell lymphoma, or non-hodgkin's lymphoma. In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia or non-hodgkin's lymphoma. In some embodiments, the hematologic malignancy is chronic lymphocytic leukemia. In other embodiments, the hematologic malignancy is non-hodgkin's lymphoma. In some embodiments, the hematologic malignancy is follicular lymphoma. In other embodiments, the hematologic malignancy is diffuse large B-cell lymphoma. In some embodiments, the compound of formula (I) is compound I or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound II or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound III or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound IV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound V or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VI or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VIII or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound IX or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound X or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XI or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XIII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound XIV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound XV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XVI or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In certain embodiments, the hematologic malignancy is a T cell malignancy. In certain embodiments, the T cell malignancy comprises peripheral T cell lymphoma (PTCL-NOS), anaplastic large cell lymphoma, angioimmunoblastic lymphoma, cutaneous T cell lymphoma, adult T cell leukemia/lymphoma (ATLL), blastic NK cell lymphoma, enteropathy-type T cell lymphoma, hepatosplenic gamma-T cell lymphoma, lymphoblastic lymphoma, nasal NK/T cell lymphoma, or treatment-related T cell lymphoma not otherwise specified.

In certain embodiments, the hematologic malignancy is a B cell malignancy. In certain embodiments, the B cell malignancy comprises Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), acute monocytic leukemia (AMoL), Chronic Lymphocytic Leukemia (CLL), high risk Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, burkitt's lymphoma, non-burkitt high grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), small lymphocytic lymphoma (FL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), waldenstrom macroglobulinemia, multiple, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma or lymphomatoid granulomatosis. In certain embodiments, the B cell malignancy is Diffuse Large B Cell Lymphoma (DLBCL). In certain embodiments, the hematologic malignancy is diffuse large B-cell lymphoma (DLBCL). In certain embodiments, the DLBCL is activated B-cell DLBCL (ABC-DLBCL), germinal center B-cell-like DLBCL (GBC-DLBCL), secondary blow (double hit) DLBCL (DH-DLBCL), or tertiary blow DLBCL (TH-DLBCL). In certain embodiments, the hematologic malignancy is relapsed refractory diffuse large B-cell lymphoma (r/r DLBCL).

In some embodiments, the hematologic malignancy is B-cell non-hodgkin lymphoma (NHL). In some embodiments, the hematologic malignancy is B-cell indolent non-hodgkin lymphoma (NHL). In certain embodiments, the B cell malignancy is selected from Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), marginal zone B cell lymphoma (MZL), Diffuse Large B Cell Lymphoma (DLBCL), and high grade non-hodgkin's lymphoma. In certain embodiments, the B cell malignancy is selected from Chronic Lymphocytic Leukemia (CLL), Follicular Lymphoma (FL), marginal zone B cell lymphoma (MZL), or Diffuse Large B Cell Lymphoma (DLBCL).

In certain embodiments, the hematologic malignancy is a relapsed or refractory hematologic malignancy. In certain embodiments, the relapsed or refractory hematologic malignancy is a relapsed or refractory T-cell malignancy. In certain embodiments, the relapsed or refractory hematologic malignancy is a relapsed or refractory B-cell malignancy. In some embodiments, the cancer is relapsed B-cell non-hodgkin's lymphoma (NHL) or Chronic Lymphocytic Leukemia (CLL). In some embodiments, the hematologic malignancy is recurrent B-cell non-hodgkin lymphoma (NHL) or Chronic Lymphocytic Leukemia (CLL).

Some embodiments provided herein describe methods of treating or preventing a proliferative disease or disorder comprising administering a PI3K inhibitor in combination with a BTK inhibitor. In some embodiments, provided herein are methods of preventing relapse of a proliferative disease or disorder, comprising administering a PI3K inhibitor in combination with a BTK inhibitor. In some embodiments, provided herein are methods of achieving and maintaining partial cancer remission, comprising administering a PI3K inhibitor in combination with a BTK inhibitor. In some embodiments, provided herein are methods of achieving and maintaining complete cancer remission, comprising administering a PI3K inhibitor in combination with a BTK inhibitor. In some embodiments, the combination therapy of a PI3K inhibitor (e.g., a compound of formula (I)) with a BTK inhibitor (e.g., BGB-3111) described herein provides a synergistic effect. In some embodiments, the combination therapy of a PI3K inhibitor (e.g., a compound of formula (I)) with a BTK inhibitor (e.g., BGB-3111) described herein provides synergistic anti-tumor or anti-cancer activity. In certain embodiments, the combination therapies described herein allow for the use of lower doses of PI3K inhibitor and/or BTK inhibitor (e.g., BGB-3111). In some embodiments, the combination therapies described herein allow for less frequent administration of a PI3K inhibitor and/or a BTK inhibitor (e.g., BGB-3111) to a subject. In some embodiments, the combination therapies described herein reduce toxicity associated with administration of a PI3K inhibitor and/or a BTK inhibitor (e.g., BGB-3111) to a subject without reducing efficacy in preventing, controlling, treating, or ameliorating cancer, such as chronic lymphocytic leukemia. In some embodiments, the synergistic effects observed with the combination therapies described herein result in an increase in the efficacy of the therapy in preventing, managing, treating, or ameliorating cancer, such as chronic lymphocytic leukemia.

In some embodiments, the combination therapies described herein avoid or reduce adverse or unwanted side effects associated with the use of PI3K inhibitors and/or BTK inhibitors (e.g., BGB-3111).

In some embodiments, the combination therapies described herein avoid or reduce adverse or unwanted side effects associated with the use of PI3K inhibitors and/or BTK inhibitors. In some embodiments, the combination therapies described herein avoid, reduce, or minimize the risk of death due to infection. In some embodiments, the combination therapies described herein avoid, reduce, or minimize infection, neutropenia, diarrhea/colitis, elevated liver transaminases (alanine/aspartate aminotransferase > 5 times the upper limit of the normal range), pneumonia, rash, liver damage, kidney damage, fever, elevated triglycerides, or combinations thereof in a patient receiving the combination therapy. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of infection associated with the use of PI3K inhibitors and/or BTK0 inhibitors. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of neutropenia. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of diarrhea/colitis. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of elevated liver transaminase. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of pneumonia. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of skin rash. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of liver or kidney damage. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of fever. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of triglyceride elevation. In certain embodiments, the combination therapies described herein avoid, reduce or minimize enterocolitis (manifested by diarrhea), skin toxicity, liver toxicity (manifested by elevated transaminases), pulmonary toxicity (manifested by noninfectious pneumonia), infection, or a combination thereof.

In some embodiments, the combination therapies described herein provide a high objective response rate (OR), as determined by assessment of tumors by radiology and/OR physical examination. In some embodiments, the combination therapies described herein provide a sustained response (DR) and/or an increased sustained response rate (DRR; continuous response [ complete or partial objective response ] initiated within 12 months of treatment and lasting ≧ 6 months) in a subject or patient. In some embodiments, the combination therapy described herein provides complete remission. In some embodiments, the combination therapies described herein provide a better response than monotherapy with a compound of formula (I) and/or a BTK0 inhibitor. In some embodiments, the combination therapy described herein provides complete remission beginning within 12 months of treatment and lasting ≧ 6 months. In some embodiments, the combination therapies described herein provide Complete Response (CR) and/or no signs of disease (NED) starting within 12 months of treatment and lasting ≧ 6 months.

In some embodiments, the combination therapy described herein avoids, reduces, or minimizes infection, neutropenia, diarrhea, pneumonia, anemia, thrombocytopenia, nausea, vomiting, limb swelling, or a combination thereof in a patient receiving the combination therapy. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of infection. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of neutropenia. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of diarrhea/colitis. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of pneumonia or focal pneumonia. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of anemia. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of thrombocytopenia. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of nausea. In certain embodiments, the combination therapies described herein avoid, reduce, or minimize the incidence of emesis. In certain embodiments, the combination therapy described herein avoids, reduces, or minimizes the incidence of limb swelling.

Resistance, recurrence or refractory refers to a decrease in the responsiveness of a cancer to treatment, e.g., up to the point in time when the cancer is unresponsive to treatment. The cancer may be resistant at the beginning of the treatment, or may become resistant during the treatment. The term "refractory" may refer to a cancer for which treatment (e.g., chemotherapeutic drugs, biologicals, and/or radiation therapy) has been proven ineffective. Refractory cancer tumors may shrink, but not to the extent that treatment is certainly effective. However, in general, tumors either remain the same size as before treatment (stable disease), or grow (disease progression).

Depending on the disorder, disease or condition to be treated and the condition of the subject, the compounds or pharmaceutical compositions provided herein can be administered by oral, parenteral (e.g., intramuscular, intraperitoneal, intravenous, ICV, intracisternal injection or infusion, subcutaneous injection or implant), inhalation, nasal, vaginal, rectal, sublingual, or topical (e.g., transdermal or topical) routes of administration, and can be formulated, alone or together, in suitable dosage units with pharmaceutically acceptable excipients, carriers, adjuvants and vehicles appropriate for each route of administration described elsewhere herein.

Dosage and dosing regimen

In certain embodiments, the methods provided herein comprise administering to a patient a compound of formula (I), or an isotopically variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a BTK inhibitor (e.g., BGB-3111 or zanubbrutinib), either simultaneously or sequentially by the same or different routes of administration.

The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the bloodstream) and the disease being treated.

In certain embodiments, the compound of formula (I) or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and the BTK inhibitor are administered simultaneously or sequentially at substantially the same time. If administered sequentially, the BTK inhibitor may be administered before or after administration of the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the BTK inhibitor is administered prior to the administration of the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the BTK inhibitor is administered concurrently with the administration of the compound of formula (I), an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the BTK inhibitor is administered after administration of the compound of formula (I), an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof.

The compound of formula (I), or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and the BTK inhibitor need not be administered by means of the same vehicle. In some embodiments, the BTK inhibitor and the compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, are administered in different vehicles. The BTK inhibitor may be administered one or more times, and the number of administrations of each component of the combination may be the same or different. In addition, the compound of formula (I) or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and the BTK inhibitor need not be administered at the same site.

In some cases, the methods described herein further comprise administering the PI3K inhibitor in combination with a BTK inhibitor to a subject or patient in need thereof in a plurality of cycles, the cycles repeating on a regular schedule, with a rest period between each cycle. For example, in some cases, treatment is given for one week, followed by a rest for three weeks, which is one treatment cycle.

In some cases, one cycle comprises administration of a PI3K inhibitor concurrently with administration of a BTK inhibitor. In some cases, the PI3K inhibitor and the BTK inhibitor are administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.

In some cases, one cycle comprises administration of the PI3K inhibitor followed by administration of the BTK inhibitor. In some cases, the PI3K inhibitor is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days, followed by administration of the BTK inhibitor for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

In some cases, one cycle comprises administration of a PI3K inhibitor first, followed by concurrent administration of a BTK inhibitor. In some cases, the PI3K inhibitor is administered first for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days, followed by concurrent administration of the BTK inhibitor for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some cases, the PI3K inhibitor is administered first for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, or about 7 days, followed by concurrent administration of the BTK inhibitor for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some cases, the PI3K inhibitor is administered first for about 7 days, followed by concurrent administration of the BTK inhibitor for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days. In some cases, the PI3K inhibitor is administered first for about 7 days, followed by concurrent administration of the BTK inhibitor for about 10 days, about 11 days, about 12 days, about 13 days, or about 14 days.

In some cases, one cycle includes administration of only PI3K inhibitor. In some cases, the PI3K inhibitor is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.

In some cases, a cycle includes administration of only a BTK inhibitor. In some cases, the BTK inhibitor is administered for about 1 day, about 2 days, about 3 days, about 4 days, about 5 days, about 6 days, about 7 days, about 8 days, about 9 days, about 10 days, about 11 days, about 12 days, about 13 days, about 14 days, about 15 days, about 16 days, about 17 days, about 18 days, about 19 days, about 20 days, about 21 days, about 22 days, about 23 days, about 24 days, about 25 days, about 26 days, about 27 days, or about 28 days.

In some cases, the method for multi-cycle chemotherapy comprises administering a second cycle within about 60 days or about 3 months. In some cases, the method for multi-cycle chemotherapy comprises administering a second cycle within 50 days. In another instance, the second period is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 day after the first period. In some embodiments, any additional cycles of administration are within 50 days after the previous cycle. In some embodiments, any additional cycles of administration are within 10 days after the previous cycle. In some embodiments, the administration of any additional cycles is within 9 days after the previous cycle. In some embodiments, any additional cycles of administration are within 8 days after the previous cycle. In some embodiments, any additional cycles of administration are within 7 days after the previous cycle. In some embodiments, any additional cycles of administration are within 6 days after the previous cycle. In some embodiments, any additional cycles of administration are within 5 days after the previous cycle. In some embodiments, any additional cycles of administration are within 4 days after the previous cycle. In some embodiments, the administration of any additional cycle is within 3 days after the previous cycle. In some embodiments, the administration of any additional cycle is within 2 days after the previous cycle. In some embodiments, any additional cycles of administration are within 1 day after the previous cycle. In another embodiment, the additional cycle is administered within 45, 40, 35, 30, 25, 21, 20, 15, 14, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1 days after the previous cycle.

The length of the treatment cycle depends on the treatment administered. In some embodiments, the length of the treatment cycle is in the range of two to six weeks. In some embodiments, the length of the treatment cycle is in the range of four to six weeks. In some embodiments, the treatment cycle is 28 days in length. In some embodiments, the length of the treatment cycle is 56 days. In some embodiments, the treatment cycle lasts for one, two, three, or four weeks. In some embodiments, the treatment cycle lasts four weeks. The number of therapeutic doses scheduled in each cycle will also vary with the drug administered.

In certain instances, a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject in a 28 day cycle. In some embodiments, a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject for at least one 28-day cycle. In some embodiments, a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject for at least two 28-day periods.

In certain embodiments, a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject for a period of up to about 7 days. In some embodiments, the number of days of administering a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is intermittent. In some embodiments, a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject for about 7 consecutive days in a 28-day cycle.

In some embodiments, the methods comprise an intermittent dosing schedule (IS) comprising administering to the subject a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for 7 consecutive days in a 28-day cycle, followed by 21 days without treatment. In some embodiments, a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject for at least one 28-day period. In some embodiments, the IS avoids or reduces adverse or unwanted side effects associated with the use of PI3K inhibitors, such as enterocolitis (manifested by diarrhea), skin toxicity, liver toxicity (manifested by elevated transaminases), pulmonary toxicity (manifested by noninfectious pneumonia), and infection. In some embodiments, the IS avoids or reduces enterocolitis, skin rash, transaminase, or a combination thereof.

In some embodiments, the methods comprise a continuous daily dosing schedule (CS) comprising administering to the subject a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for 28 consecutive days in a 28-day cycle. In some embodiments, a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is administered to a subject for at least two cycles of CS28 days. In certain instances, the methods comprise administering to the subject a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, once daily for 7 consecutive days in a 28-day period after at least two CS28 day periods for at least two periods of 28 days of a daily dosing schedule (CS) followed by an intermittent dosing schedule (IS) for 21 days without treatment. In some embodiments, the dosing schedule avoids or reduces adverse or unwanted side effects associated with the use of PI3K inhibitors, such as enterocolitis (manifested as diarrhea), skin toxicity, liver toxicity (manifested as elevated transaminases), pulmonary toxicity (manifested as noninfectious pneumonia), and infection. In some embodiments, the dosing regimen avoids or reduces enterocolitis, skin rash, transaminase, or a combination thereof.

Administering a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, in two consecutive daily dosing (CS) cycles in a treatment regimen; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, which IS then administered daily only for the first seven days of each subsequent (IS) cycle, the CS and IS cycles are 28 day cycles, wherein the IS cycle IS repeated until no further disease progression IS observed. In some or other embodiments, if disease progression is observed in the subject, the subject is re-subjected to a 28 day continuous daily dosing (CS) cycle until disease regression or stabilization is observed.

Administering a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, in a treatment regimen comprising two 28-day continuous daily dosing (CS) cycles; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, followed in certain instances only by daily administration for the first seven days of each subsequent (IS) 28-day cycle; wherein no further disease regression or stabilization IS observed in the subject over the intermittent dosing schedule (IS) period, the subject IS re-subjected to a 28 day continuous daily dosing (CS) period until disease regression or stabilization IS observed.

In some embodiments, the compound of formula (I) is compound I or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound II or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound III or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound IV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound V or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VI or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound VIII or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound IX or an isotopically variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound X or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XI or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XIII or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound XIV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the compound of formula (I) is compound XV or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) is compound XVI or an isotopic variant, pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

The suitability of a particular route of administration for a particular active agent will depend on the active agent itself (e.g., whether it can be administered orally without breaking down before entering the bloodstream) and the disease to be treated. The recommended route of administration of the second active agent is known to those of ordinary skill in the art. See, for example, Physicians' Desk Reference, 1755-.

In certain embodiments, the compound of formula (I) or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and the BTK inhibitor are administered simultaneously, at substantially the same time, or sequentially. If administered sequentially, the BTK inhibitor may be administered before or after administration of the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, the BTK inhibitor is administered prior to the administration of the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the BTK inhibitor is administered concurrently with the compound of formula (I), an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the BTK inhibitor is administered after administration of the compound of formula (I), an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. In some embodiments, the compound of formula (I) or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof and the BTK inhibitor need not be administered by means of the same vehicle. In some embodiments, the BTK inhibitor and the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, are administered in different vehicles. The BTK inhibitor may be administered one or more times, and the number of administrations of each component of the combination may be the same or different. In addition, the compound of formula (I) or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and the BTK inhibitor need not be administered at the same site.

In certain embodiments, a compound of formula (I), or an isotopic variant thereof, is administered to a patient periodically; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a BTK inhibitor. Cycling therapy involves administering an active agent or combination of active agents for a period of time, followed by a rest period of time, and repeating this sequential administration. Cycling therapy can reduce the development of resistance to one or more therapies, avoid or reduce the side effects of a therapy, and/or improve the efficacy of a treatment.

In some embodiments, the compound of formula (I) is administered daily, every other day 3 times a week, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every two weeks, every 3 times a week, every 4 times a week, every 5 times a week, every 6 times a week, monthly, twice monthly, 3 times monthly, every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In some embodiments, the compound of formula (I) is administered daily. In some embodiments, the compound of formula (I) is administered daily for a period of up to about 28 days. In some embodiments, the compound of formula (I) is administered daily for a period of up to about 7 days.

In some embodiments, the BTK inhibitor is administered daily, every other day 3 times a week, every 3 days, every 4 days, every 5 days, every 6 days, weekly, every 2 weeks, every 3 weeks, every 4 weeks, every 5 weeks, every two weeks, every 3 times a week, every 4 times a week, every 5 times a week, every 6 times a week, once a month, twice a month, 3 times a month, once every 2 months, once every 3 months, once every 4 months, once every 5 months, or once every 6 months. In some embodiments, the BTK inhibitor is administered 8 times within 6 months.

In some cases, the compound of formula (I) or BTK inhibitor is optionally administered sequentially; alternatively, the dose of drug administered is temporarily reduced or temporarily discontinued for a certain length of time (i.e., a "drug holiday"). In some embodiments, the length of the drug holiday varies between 2 days and 1 year, including, by way of example only, 2 days, 3 days, 4 days, 5 days, 6 days, 7 days, 8 days, 9 days, 10 days, 12 days, 14 days, 15 days, 20 days, 21 days, 28 days, 35 days, 50 days, 70 days, 100 days, 120 days, 150 days, 180 days, 200 days, 250 days, 280 days, 300 days, 320 days, 350 days, or 365 days. Dose reductions during the drug holiday include 10% -100%, including, by way of example only, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, or 100%.

In certain embodiments, an appropriate dosage level of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, in the treatment, prevention or amelioration of one or more symptoms of the disorders, diseases or conditions described herein is typically from about 1 to 1000mg, from about 1 to about 500mg, from about 5 to about 200mg, from about 5 to about 250mg, or from about 10 to about 150mg, which can be administered in single or multiple doses. In certain embodiments, the compound of formula (I) or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450 or 500 mg. In certain embodiments, the compound of formula (I) or isotopic variation thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 60mg, about 120mg, about 150mg or about 180 mg. In certain embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered in an amount of about 30 mg. In certain embodiments, the amount of a compound of formula (I) or isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof administered is about 45 mg. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 60 mg. In certain embodiments, a compound of formula (I) or an isotopic variant thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 35, about 40, about 45, about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 225, about 250, about 275, about 300, about 325, about 350, about 375, about 400, about 450 or about 500 mg. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 90 mg. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 120 mg. In certain embodiments, the compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered in an amount of about 150 mg. In certain embodiments, the compound of formula (I) or an isotopic variation thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered in an amount of about 180 mg.

In certain embodiments, the compound of formula (I) or an isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 450 or 500 mg/day. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 45 mg/day. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 60 mg/day. In certain embodiments, the compound of formula (I) or isotopic variation thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 90 mg/day. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 120 mg/day. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 150 mg/day. In certain embodiments, the compound of formula (I) or an isotopic variant or pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof is administered in an amount of about 180 mg/day.

For oral administration, the pharmaceutical compositions provided herein may be formulated in the form of a tablet or capsule containing from about 1.0 to about 1,000mg of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and in one embodiment, from about 1, about 5, about 10, about 15, about 20, about 25, about 30, about 45, about 50, about 60, about 75, about 90, about 100, about 120, about 150, about 180, about 200, about 250, about 300, about 400, about 500, about 600, about 750, about 800, about 900 and about 1,000mg of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, for symptomatic adjustment of the dosage to a patient to be treated.

In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a tablet containing about 45, 60, 90, 120, 150, or 180mg of a compound of formula (I), or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. The pharmaceutical composition may be administered on a regimen of 1-4 times per day, including once, twice, three times and four times per day. In some embodiments, the compound of formula (I), or isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof. In some embodiments, about 30mg, about 45mg, or about 60mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

In certain embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 45mg per day for 28 days or 56 days. In certain particular embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 45mg per day for 28 days. In other particular embodiments, the compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 45mg per day for 56 days.

In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a tablet containing about 60mg of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The pharmaceutical composition may be administered on a regimen of 1-4 times per day, including once, twice, three times and four times per day. In certain embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 60mg per day for 28 days or 56 days. In certain particular embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 60mg per day for 28 days. In other particular embodiments, the compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 60mg per day for 56 days.

In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a tablet containing about 90mg of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The pharmaceutical composition may be administered on a regimen of 1-4 times per day, including once, twice, three times and four times per day. In certain embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 90mg per day for 28 days or 56 days. In certain particular embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 90mg per day for 28 days. In other particular embodiments, the compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 90mg per day for 56 days.

In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a tablet containing about 120mg of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The pharmaceutical composition may be administered on a regimen of 1-4 times per day, including once, twice, three times and four times per day. In certain embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 120mg per day for 28 days or 56 days. In certain particular embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 120mg per day for 28 days. In other particular embodiments, the compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 120mg per day for 56 days.

In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a tablet containing about 150mg of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The pharmaceutical composition may be administered on a regimen of 1-4 times per day, including once, twice, three times and four times per day. In certain embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 150mg per day for 28 days or 56 days. In certain particular embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 150mg per day for 28 days. In other particular embodiments, the compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 150mg per day for 56 days.

In some embodiments, the pharmaceutical compositions provided herein may be formulated in the form of a tablet containing about 180mg of a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof. The pharmaceutical composition may be administered on a regimen of 1-4 times per day, including once, twice, three times and four times per day. In certain embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 180mg per day for 28 days or 56 days. In certain particular embodiments, a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 180mg per day for 28 days. In other particular embodiments, the compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is administered to a patient in need thereof in an amount of about 180mg per day for 56 days.

In methods of treating, preventing, or ameliorating one or more symptoms of a disorder, disease, or condition described herein, an appropriate dosage level of a BTK inhibitor is typically in the range of about 0.1 to 2000 milligrams per day. For example, 1-500 mg once or more daily may be effective to achieve the desired result.

In certain embodiments, the BTK inhibitor is ibrutinib, and the amount of ibrutinib administered is about 10 mg/day up to (and including) 1000 mg/day. In certain embodiments, the amount of ibrutinib administered is from about 10 mg/day to 600 mg/day. In certain embodiments, the amount of ibrutinib administered is from about 100 mg/day to 600 mg/day. In certain embodiments, the daily amount of ibrutinib administered is about 10mg, about 50mg, about 100mg, about 140mg, about 280mg, about 420mg, or about 560 mg.

In certain embodiments, the BTK inhibitor is BGB-3111, and BGB-3111 is administered in an amount of from about 10 mg/day up to (and including) 1000 mg/day. In certain embodiments, BGB-3111 is administered in an amount of from about 10 mg/day to 600 mg/day. In certain embodiments, BGB-3111 is administered in an amount of about 100 mg/day to 600 mg/day. In certain embodiments, the BGB-3111 is administered in an amount of about 10mg, about 30mg, about 45mg, about 50mg, about 100mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 400mg, about 440mg, about 480mg, about 520mg, or about 560mg per day.

In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 365, 370, 375, 400, 450, 500, or 560 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 1, 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 210, 220, 230, 240, 250, 260, 270, 280, 290, 300, 310, 320, 330, 340, 350, 360, 365, 370, 375, 400, 450, 500, or 560 mg/day. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 320 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 10mg, about 30mg, about 45mg, about 50mg, about 100mg, about 150mg, about 160mg, about 170mg, about 180mg, about 190mg, about 200mg, about 220mg, about 240mg, about 260mg, about 280mg, about 300mg, about 320mg, about 340mg, about 360mg, about 400mg, about 440mg, about 480mg, about 520mg, or about 560 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 80 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 160 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 200 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 240 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 280 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 320 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 360 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 400 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 440 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 480 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 520 mg. In certain embodiments, the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered in an amount of about 560 mg.

In some embodiments, about 30mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 160mg of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, about 30mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 160mg of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily.

In some embodiments, about 45mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 160mg of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, about 45mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 160mg of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily.

In some embodiments, about 60mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 160mg of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily. In some embodiments, about 60mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 160mg of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily.

For oral administration, the pharmaceutical compositions provided herein can be formulated in the form of a tablet or capsule containing from about 1.0 to about 1,000mg of the BTK inhibitor or a pharmaceutically acceptable salt thereof, and in one embodiment, from about 1, about 25, about 50, about 100, about 125, about 150, about 160, about 170, about 180, about 190, about 200, about 300, about 310, about 320, about 330, about 340, about 350, about 360, about 370, about 380, about 390, about 400, about 500, about 600, about 700, and about 1,000mg of the BTK inhibitor or a pharmaceutically acceptable salt thereof, for symptomatic adjustment of the dosage to the patient to be treated. The pharmaceutical composition may be administered on a regimen of 1-4 times per day, including once, twice, three times and four times per day. In certain embodiments, the BTK inhibitor is administered once daily, twice daily, three times daily, or four times daily. In certain embodiments, the BTK inhibitor is administered once daily. In certain embodiments, the BTK inhibitor is administered twice daily. In some embodiments, about 320mg of the BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered once daily. In some embodiments, about 160mg BTK inhibitor, or a pharmaceutically acceptable salt thereof, is administered twice daily.

In certain embodiments, the BTK inhibitor is co-administered once daily (e.g., in a single dosage form). In certain embodiments, the BTK inhibitor is co-administered twice daily (e.g., in a single dosage form).

In certain embodiments, about 30mg, about 45mg, or about 60mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 160mg of a BTK inhibitor (e.g., BGB-3111) is administered twice daily. In certain embodiments, about 30mg, about 45mg, or about 60mg of a compound of formula (I), or an isotopic variant thereof, is administered once daily; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and about 320mg of a BTK inhibitor (e.g., BGB-3111) is administered once daily.

It will be understood, however, that the specific dose level and frequency of dosage for any particular patient may be varied and will depend upon a variety of factors including the activity of the specific compound employed, the metabolic stability and length of action of that compound, the age, body weight, general health, sex, diet, mode and time of administration, rate of excretion, drug combination, the severity of the particular condition, and the host undergoing therapy.

Additional combination therapy

In certain embodiments, the combination therapy methods comprising a compound of formula (I), an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a BTK inhibitor can also be used in combination or combination with a third agent or therapy useful for treating, preventing, or ameliorating one or more symptoms of a proliferative disorder, disease, or condition.

Suitable third therapeutic agents may also include, but are not limited to: (1) an alpha-adrenergic agent; (2) antiarrhythmic drugs; (3) antiatherosclerotic agents, such as ACAT inhibitors; (4) antibiotics, such as anthracyclines, bleomycin, mitomycin, dactinomycin and plicamycin; (5) anticancer drugs and cytotoxic agents, for example, alkylating agents such as nitrogen mustards, alkyl sulfonates, nitrosoureas, vinyl imines, and triazenes; (6) anticoagulants, such as nitre coumarin, argatroban, bivalirudin, lepirudin, fondaparinux, heparin, phenindione, warfarin, and ximelagatran; (7) antidiabetic drugs such as biguanides (e.g., metformin), glucosidase inhibitors (e.g., acarbose), insulin, meglitinides (e.g., repaglinide), sulfonylureas (e.g., glimepiride, glyburide, and glipizide), thiazolidinediones (e.g., troglitazone, rosiglitazone, and pioglitazone), and PPAR- γ agonists; (8) antifungal agents, such as amorolfine, amphotericin B, anidulafungin, bifonazole, butenafine, butoconazole, caspofungin, ciclopirox, clotrimazole, econazole, fenticonazole, felodipine, fluconazole, isoconazole, itraconazole, ketoconazole, micafungin, miconazole, naftifine, natamycin, nystatin, oxiconazole, ravuconazole, posaconazole, rimycin, sertaconazole, sulconazole, terbinafine, terconazole, tioconazole, and voriconazole; (9) anti-inflammatory agents, for example, non-steroidal anti-inflammatory agents, such as anti-inflammatory agents, e.g., aceclofenac, acemetacin, amoxiprin, aspirin, apazone, benorilate, bromfenac, carprofen, celecoxib, choline magnesium salicylate, diclofenac, diflunisal, etodolac, etoricoxib, aminosalicylic acid (faislamine), fenbufen, fenoprofen, flurbiprofen, ibuprofen, indomethacin, ketoprofen, ketorolac, lornoxicam, loxoprofen, lumiracoxib, meclofenamic acid, mefenamic acid, meloxicam, analgin, methyl salicylate, magnesium salicylate, nabumetone, naproxen, nimesulide, oxyphenbutazone, parecoxib, phenylbutazone, piroxicam, salsalate, sulindac, sulpirenone, suprofen, tenoxicam, tiaprofenic acid, and tolmetin; (10) antimetabolites such as folic acid antagonists, purine analogs, and pyrimidine analogs; (11) antiplatelet drugs such as GPIIb/IIIa blockers (e.g., abciximab, eptifibatide, and tirofiban), P2Y (AC) antagonists (e.g., clopidogrel, ticlopidine, and CS-747), cilostazol, dipyridamole, and aspirin; (12) antiproliferative agents, such as methotrexate, FK506 (tacrolimus), and mycophenolate mofetil; (13) anti-TNF antibodies or soluble TNF receptors such as etanercept, rapamycin, and leflunomide (leflunimide); (14) an aP2 inhibitor; (15) beta-adrenergic drugs, such as carvedilol and metoprolol; (16) bile acid sequestrants, such as cholestyramine; (17) calcium channel blockers such as amlodipine besylate; (18) a chemotherapeutic agent; (19) cyclooxygenase-2 (COX-2) inhibitors such as celecoxib and rofecoxib; (20) (ii) a cyclosporin; (21) cytotoxic drugs such as azathioprine and cyclophosphamide; (22) diuretics, such as chlorothiazide, hydrochlorothiazide, flumethiazide, hydroflumethiazide, bendroflumethiazide, meclorthiazide, trichlorthiazide, polythiazide, benzothiazine, ethacrynic acid, tennic acid, chlorthalidone, furosemide, moxazolide, bumetanide, triamterene, amiloride and spironolactone; (23) endothelin-converting enzyme (ECE) inhibitors such as phosphoramidon; (24) enzymes, such as L-asparaginase; (25) factor VIIa inhibitors and factor Xa inhibitors; (26) farnesyl protein transferase inhibitors; (27) a fibrate; (28) growth factor inhibitors, such as modulators of PDGF activity; (29) a growth hormone secretagogue; (30) HMG-CoA reductase inhibitors such as pravastatin, lovastatin, atorvastatin, simvastatin, NK-104 (also known as itavastatin, nivastatin or nisstatin) and ZD-4522 (also known as rosuvastatin, atorvastatin or visstatin); neutral Endopeptidase (NEP) inhibitors; (31) hormonal agents such as glucocorticoids (e.g., cortisone), estrogens/antiestrogens, androgens/antiandrogens, progestins, luteinizing hormone-releasing hormone antagonists, and octreotide acetate; (32) an immunosuppressant; (33) mineralocorticoid receptor antagonists such as spironolactone and eplerenone; (34) microtubule disrupting agents, such as ecteinascidins; (35) microtubule stabilizing agents such as paclitaxel, docetaxel and epothilone A-F; (36) an MTP inhibitor; (37) nicotinic acid; (38) phosphodiesterase inhibitors, such as PDE III inhibitors (e.g., cilostazol) and PDE V inhibitors (e.g., sildenafil, tadalafil and vardenafil); (39) products of plant origin, such as vinca alkaloids, epipodophyllotoxins and taxanes; (40) platelet Activating Factor (PAF) antagonists; (41) platinum coordination complexes, such as cisplatin, satraplatin, and carboplatin; (42) a potassium channel opener; (43) prenyl-protein transferase inhibitors; (44) protein tyrosine kinase inhibitors; (45) a renin inhibitor; (46) a squalene synthetase inhibitor; (47) steroids, such as aldosterone, beclomethasone, betamethasone, deoxycorticosterone acetate, fludrocortisone, hydrocortisone (cortisol), prednisolone, prednisone, methylprednisolone, dexamethasone, and triamcinolone; (48) TNF- α inhibitors, such as tenidap; (49) thrombin inhibitors, such as hirudin; (50) thrombolytic agents such as aniplase, reteplase, tenecteplase, tissue plasminogen activator (tPA), recombinant tPA, streptokinase, urokinase, prourokinase, and Anisylated Plasminogen Streptokinase Activator Complex (APSAC); (51) thromboxane receptor antagonists such as ifetroban; (52) a topoisomerase inhibitor; (53) vasopeptidase inhibitors (dual NEP-ACE inhibitors), such as omapatrila and gemotrila; and (54) other miscellaneous drugs, such as hydroxyurea, procarbazine, mitotane, hexamethylmelamine, and gold compounds.

In certain embodiments, the third therapy that may be used in conjunction with the methods provided herein includes, but is not limited to, surgery, endocrine therapy, biological response modifiers (e.g., interferons, interleukins, and Tumor Necrosis Factor (TNF)), hyperthermia and cryotherapy, and drugs that attenuate any adverse effects (e.g., antiemetics).

In certain embodiments, the third therapeutic agents that may be used in combination with the compounds provided herein include, but are not limited to, alkylating drugs (nitrogen mustards, chlorambucil, cyclophosphamide, melphalan, and ifosfamide), antimetabolites (cytarabine (also known as cytosine arabinoside or Ara-C), and methotrexate), purine and pyrimidine antagonists (6-mercaptopurine, 5-fluorouracil, cytarabine, and gemcitabine), spindle poisons (vinblastine, vincristine, and vinorelbine), podophyllotoxins (etoposide, irinotecan, and topotecan), antibiotics (daunorubicin, doxorubicin, bleomycin, and mitomycin), nitrosoureas (carmustine and lomustine), enzymes (asparaginase), hormones (tamoxifen, leuprolide, flutamide, and megestrol), Imatinib, doxorubicin, dexamethasone, and cyclophosphamide. For a more complete discussion of newer cancer therapies, see http:// www.nci.nih.gov/, a list of FDA-approved oncology drugs is http:// www.fda.gov/cder/cancer/dniglistframe. htm, and The Merck Manual, 17 th edition 1999, The entire contents of which are incorporated herein by reference.

In another embodiment, the methods provided herein comprise administering a compound of formula (I), or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a BTK inhibitor, together with one or more chemotherapeutic agents and/or therapies selected from: alkylating agents (e.g., cisplatin, carboplatin); antimetabolites (e.g., methotrexate and 5-FU); anti-tumor antibiotics (e.g., doxorubicin and bleomycin); anti-tumor plant alkaloids (e.g., paclitaxel and etoposide); anti-tumor hormones (e.g., dexamethasone and tamoxifen), anti-tumor immune agents (e.g., interferon alpha, beta, gamma); radiotherapy; and surgery. In certain embodiments, the one or more chemotherapeutic agents and/or therapies are administered to the subject before, during, or after administration of the compound of formula (I) or isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and the BTK inhibitor.

Such other agents or drugs may be administered by their usual routes and in their usual amounts, either simultaneously or sequentially with the compound of formula (I) or isotopically variant thereof or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and the BTK inhibitor. When the compound of formula (I) and the BTK inhibitor are used concurrently with one or more other drugs, a pharmaceutical composition containing such other drugs in addition to the compound of formula (I) or its isotopic variant or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof and the BTK inhibitor may be used, but is not required. Accordingly, the pharmaceutical compositions provided herein include those that contain one or more other active ingredients or therapeutic agents in addition to the compound of formula (I).

Pharmaceutical compositions and routes of administration

Provided herein is a pharmaceutical composition comprising a compound provided herein (a compound of formula (I) and/or a BTK inhibitor) and a pharmaceutically acceptable excipient, adjuvant, carrier, buffer or stabilizer. In some embodiments, the compound of formula (I) and the BTK inhibitor are present in the same pharmaceutical composition. In some embodiments, the compound of formula (I) and the BTK inhibitor are in different pharmaceutical compositions.

In one embodiment, the pharmaceutical composition is provided in a dosage form for oral administration comprising a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. The pharmaceutical compositions provided herein formulated for oral administration may be in the form of tablets, capsules, powders, or liquids. In some embodiments, the tablet comprises a solid carrier or adjuvant. Liquid pharmaceutical compositions typically comprise a liquid carrier such as water, petroleum, animal or vegetable oil, mineral oil or synthetic oil. Physiological saline solution, dextrose or other sugar solution, or glycols such as ethylene glycol, propylene glycol or polyethylene glycol may be included. In some embodiments, the capsule comprises a solid carrier such as gelatin.

In another embodiment, the pharmaceutical composition is provided in a dosage form for parenteral administration comprising a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers. When the pharmaceutical composition can be formulated for intravenous, cutaneous or subcutaneous injection, the active ingredient is in the form of a parenterally acceptable aqueous solution, which is pyrogen-free and has suitable pH, isotonicity and stability. Suitable solutions are well within the skill of the relevant art using, for example, isotonic vehicles such as sodium chloride injection, ringer's injection, or lactated ringer's injection. In some embodiments, preservatives, stabilizers, buffers, antioxidants, and/or other additives are included as desired.

In yet another embodiment, the pharmaceutical composition is provided in a dosage form for topical administration comprising a compound provided herein, and one or more pharmaceutically acceptable excipients or carriers.

The pharmaceutical compositions may also be formulated as modified release dosage forms, including delayed release, extended release (extended), extended release (prolonged), sustained release, pulsatile release, controlled release, accelerated release, rapid release, targeted release and programmed release, as well as gastric retentive dosage forms. These dosage forms can be prepared according to conventional methods and techniques known to those skilled in The art (see Remington: The Science and Practice of Pharmacy, supra; Modified-Release Drug Delivery Technology, 2 nd edition, edited by Rathbone et al, Marcel Dekker, Inc.: New York, NY, 2008).

The pharmaceutical compositions provided herein can be provided in unit dosage form or in multiple dosage form. Unit dosage forms as used herein refer to physically discrete units suitable for administration to human and animal subjects and packaged separately as is known in the art. Each unit dose contains a predetermined amount of the active ingredient sufficient to produce the desired therapeutic effect in association with the required pharmaceutical carrier or excipient. Examples of unit dosage forms include ampoules, syringes and individually packaged tablets and capsules. The unit dosage form can be administered in several or more divided doses. A multiple dosage form is a plurality of identical unit dosage forms packaged in a single container so as to be administered in separate unit dosage forms. Examples of multi-dose forms include vials, bottles, or pints or gallons containing tablets or capsules.

The pharmaceutical compositions provided herein can be administered once, or multiple times at time intervals. It will be understood that the precise dosage and duration of treatment may vary depending on the age, weight and condition of the patient being treated, and may be determined empirically using known test protocols or by extrapolation from in vivo or in vitro test or diagnostic data. It is further understood that for any particular individual, the specific dosage regimen will be adjusted over time according to the individual need and the professional judgment of the person administering the formulation or supervising the administration of the formulation.

In certain embodiments, the pharmaceutical compositions provided herein further comprise one or more chemotherapeutic agents as defined herein.

A. Oral administration

Pharmaceutical compositions provided herein for oral administration can be provided in solid, semi-solid, or liquid dosage forms for oral administration. As used herein, oral administration also includes buccal, lingual and sublingual administration. Suitable oral dosage forms include, but are not limited to, tablets, dragees (fastmelts), chewable tablets, capsules, pills, strips (strips), troches, lozenges, troches, cachets, pellets, medicated chewing gums, bulk powders, effervescent or non-effervescent powders or granules, oral thin sprays, solutions, emulsions, suspensions, sachets (wafers), capsule sprinkles (sprinkles), elixirs, and syrups. In addition to the active ingredient, the pharmaceutical composition may contain one or more pharmaceutically acceptable carriers or excipients, including, but not limited to, binders, fillers, diluents, disintegrants, wetting agents, lubricants, glidants, colorants, dye migration inhibitors, sweeteners, flavoring agents, emulsifiers, suspending and dispersing agents, preservatives, solvents, non-aqueous liquids, organic acids, and carbon dioxide sources.

The binder or granulating agent imparts a cohesive force to the tablet to ensure that the tablet remains intact after compression. Suitable binders or granulating agents include, but are not limited to, starches, such as corn STARCH, potato STARCH, and pregelatinized STARCH (e.g., STARCH 1500); gelatin; sugars such as sucrose, glucose, dextrose, molasses, and lactose; natural and synthetic gums such as acacia, alginic acid, alginates, Irish moss extract, panwar gum, gum ghatti, isabgol hide mucilage, carboxymethylcellulose, methylcellulose, polyvinylpyrrolidone (PVP), Veegum, larch arabinogalactan, tragacanth gum powder, and guar gum; celluloses such as ethyl cellulose, cellulose acetate, calcium carboxymethyl cellulose, sodium carboxymethyl cellulose, methyl cellulose, hydroxyethyl cellulose (HEC), hydroxypropyl cellulose (HPC), hydroxypropyl methyl cellulose (HPMC); microcrystalline celluloses, such as AVICEL-PH-101, AVICEL-PH-103, AVICELRC-581, AVICEL-PH-105(FMC Corp., Marcus Hook, Pa.); and mixtures thereof. Suitable fillers include, but are not limited to, talc, calcium carbonate, microcrystalline cellulose, cellulose powder, dextrates, kaolin, mannitol, silicic acid, sorbitol, starch, pregelatinized starch, and mixtures thereof. The amount of binder or filler in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. In the pharmaceutical compositions provided herein, from about 50% to about 99% by weight of the binder or filler may be present.

Suitable diluents include, but are not limited to, dicalcium phosphate, calcium sulfate, lactose, sorbitol, sucrose, inositol, cellulose, kaolin, mannitol, sodium chloride, dry starch, and powdered sugar. Some diluents, such as mannitol, lactose, sorbitol, sucrose, and inositol, when present in sufficient amounts, can impart properties to some compressed tablets, allowing them to disintegrate in the mouth by chewing. Such compressed tablets may be used as chewable tablets. The amount of diluent in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art.

Suitable disintegrants include, but are not limited to, agar; bentonite; cellulose such as methyl cellulose and carboxymethyl cellulose; a wood product; a natural sponge; a cation exchange resin; alginic acid; gums, such as guar gum and veegum hv; citrus pulp; crosslinked celluloses, such as crosslinked carboxymethylcellulose; crosslinked polymers, such as crospovidone; cross-linked starch; calcium carbonate; microcrystalline cellulose, such as sodium starch glycolate; potassium polycrystallin; starches, such as corn starch, potato starch, tapioca starch, and pregelatinized starch; clay; align; and mixtures thereof. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. The amount of disintegrant in the pharmaceutical compositions provided herein varies with the type of formulation and is readily discernible to one of ordinary skill in the art. The pharmaceutical compositions provided herein can comprise from about 0.5% to about 15% or from about 1% to about 5% by weight of a disintegrant.

Suitable lubricants include, but are not limited to, calcium stearate; magnesium stearate; mineral oil; light mineral oil; glycerol; sorbitol; mannitol; glycols, such as glyceryl behenate and polyethylene glycol (PEG); stearic acid; sodium lauryl sulfate; talc; hydrogenated vegetable oils including peanut oil, cottonseed oil, sunflower oil, sesame oil, olive oil, corn oil and soybean oil; zinc stearate; ethyl oleate; ethyl laurate; agar; starch; stone loosening; silica or silica gels, e.g.

200(w.r.grace co., Baltimore, MD) and

(Cabot co., Boston, MA); and mixtures thereof. The pharmaceutical compositions provided herein can comprise from about 0.1% to about 5% by weight of the lubricant.

Suitable glidants include, but are not limited to, colloidal silicon dioxide,

(Cabot co. of Boston, MA) and asbestos-free talc. Suitable coloring agents include, but are not limited to, any approved, water-soluble FD&A C dye, and a water-insoluble FD suspended on hydrated alumina&C dyes, and lakes and mixtures thereof. Lakes are combinations that result in an insoluble form of a dye by absorbing a water soluble dye into a heavy metal hydrous oxide. Suitable flavoring agents include, but are not limited to, natural flavors extracted from plants such as fruits, and synthetic compound mixtures that produce a pleasant taste sensation such as peppermint and methyl salicylate. Suitable sweeteners include, but are not limited to, sucrose, lactose, mannitol, syrups, glycerol, and artificial sweeteners such as saccharin and aspartame. Suitable emulsifying agents include, but are not limited to, gelatin, gum acacia, gum tragacanth, bentonite, and surfactants such as polyoxyethylene sorbitan monooleate (R: (R) (R))

20) Polyoxyethylene sorbitan monooleate 80 (A)

80) And triethanolamine oleate. Suitable suspending and dispersing agents include, but are not limited to, sodium carboxymethylcellulose, pectin, gum tragacanth, Veegum, acacia, sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable preservatives include, but are not limited to, glycerin, methyl and propyl parabens, benzoic acid, sodium benzoate, and alcohol. Suitable wetting agents include, but are not limited to, propylene glycol monostearate, sorbitan monooleate, diethylene glycol monolaurate, and polyoxyethylene lauryl ether. Suitable solventsAgents include, but are not limited to, glycerin, sorbitol, ethanol, and syrup. Suitable non-aqueous liquids for use in the emulsion include, but are not limited to, mineral oil and cottonseed oil. Suitable organic acids include, but are not limited to, citric acid and tartaric acid. Suitable sources of carbon dioxide include, but are not limited to, sodium bicarbonate and sodium carbonate.

It will be appreciated that many carriers and excipients may serve several functions, even in the same dosage form.

Pharmaceutical compositions provided herein for oral administration may be provided as compressed tablets, molded tablets, chewable lozenges, fast-dissolving tablets, multiple-compressed tablets, or enteric-coated tablets, sugar-coated tablets, or film-coated tablets. Enteric coated tablets are compressed tablets coated with a substance that resists the action of gastric acid but dissolves or disintegrates in the intestine, thereby protecting the active ingredient from the acidic environment of the stomach. Enteric coatings include, but are not limited to, fatty acids, fats, phenyl salicylate, waxes, shellac, ammoniated shellac, and cellulose acetate phthalate. Sugar-coated tablets are compressed tablets coated with a sugar coating, which advantageously masks unpleasant tastes or odors and protects the tablets from oxidation. Film-coated tablets are compressed tablets covered with a thin layer or film of water-soluble material. Film-coated tablets include, but are not limited to, hydroxyethyl cellulose, sodium carboxymethyl cellulose, polyethylene glycol 4000, and cellulose acetate phthalate. Film coatings offer the same commonality as sugar coatings. Multiple compressed tablets are compressed tablets made by more than one compression cycle, which include layered tablets and compression-coated or dry-coated tablets.

Tablet dosage forms may be prepared from the active ingredient in powdered, crystalline, or granular form, alone or in combination with one or more carriers or excipients described herein, including binders, disintegrants, controlled release polymers, lubricants, diluents, and/or colorants. Flavoring and sweetening agents are particularly useful in the formation of chewable tablets and lozenges.

Pharmaceutical compositions provided herein for oral administration can be provided as soft or hard capsules, which can be made from gelatin, methylcellulose, starch, or calcium alginate. Hard gelatin capsules, also known as Dry Fill Capsules (DFC), are composed of two parts, one inserted into the other; thus completely encapsulating the active ingredient. Soft Elastic Capsules (SEC) are soft, spherical shells, such as gelatin shells, which are plasticized by the addition of glycerol, sorbitol or similar polyols. The soft gelatin shell may contain a preservative to prevent microbial growth. Suitable preservatives are those as described herein, including methylparaben and propylparaben, and sorbic acid. The liquid, semi-solid, and solid dosage forms provided herein can be encapsulated in a capsule. Suitable liquid and semi-solid dosage forms include solutions and suspensions of propylene carbonate, vegetable oils or triglycerides. Capsules containing such solutions may be prepared as described in U.S. patents 4,328,245, 4,409,239, and 4,410,545. The capsules may also be coated as known to those skilled in the art to improve or maintain dissolution of the active ingredient.

Coloring and flavoring agents may be used in all of the above dosage forms.

Pharmaceutical compositions provided herein for oral administration may be formulated as immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

B. Parenteral administration

The pharmaceutical compositions provided herein can be administered parenterally by injection, infusion, or implantation for local or systemic administration. Parenteral administration as used herein includes intravenous, intraarterial, intraperitoneal, intrathecal, intraventricular, intraurethral, intrasternal, intracranial, intramuscular, intrasynovial, intravesical and subcutaneous administration.

Pharmaceutical compositions provided herein for parenteral administration can be formulated in any dosage form suitable for parenteral administration, including solutions, suspensions, emulsions, micelles, liposomes, microspheres, nanosystems and solid forms suitable for solution or suspension in a liquid prior to injection. Such dosage forms can be prepared according to conventional methods known to those skilled in The art of pharmaceutical Science (see Remington: The Science and Practice of Pharmacy, supra).

Pharmaceutical compositions intended for parenteral administration may contain one or more pharmaceutically acceptable carriers and excipients, including but not limited to aqueous vehicles, water-miscible vehicles, non-aqueous vehicles, antimicrobial or preservative agents that resist microbial growth, stabilizers, solubility enhancers, isotonicity agents, buffers, antioxidants, local anesthetics, suspending and dispersing agents, wetting or emulsifying agents, complexing agents, sequestering or chelating agents, cryoprotectants (cryoprotectants), lyoprotectants (lyoprotectants), thickening agents, pH adjusting agents, and inert gases.

Suitable aqueous vehicles include, but are not limited to, water, saline, normal or Phosphate Buffered Saline (PBS), sodium chloride injection, ringer's injection, isotonic glucose injection, sterile water injection, dextrose, and lactated ringer's injection. Suitable non-aqueous vehicles include, but are not limited to, fixed oils of vegetable origin, castor oil, corn oil, cottonseed oil, olive oil, peanut oil, peppermint oil, safflower oil, sesame oil, soybean oil, hydrogenated vegetable oils, hydrogenated soybean oil, and the medium chain triglycerides of coconut oil, and palm seed oil. Suitable water-miscible vehicles include, but are not limited to, ethanol, 1, 3-butanediol, liquid polyethylene glycols (e.g., polyethylene glycol 300 and polyethylene glycol 400), propylene glycol, glycerol, N-methyl-2-pyrrolidone, N-dimethylacetamide, and dimethylsulfoxide.

Suitable antimicrobial agents or preservatives include, but are not limited to, phenol, cresol, mercuric preparations, benzyl alcohol, chlorobutanol, methyl and propyl parabens, thimerosal, benzalkonium chloride (e.g., benzethonium chloride), methyl paraben, propyl paraben, and sorbic acid. Suitable isotonic agents include, but are not limited to, sodium chloride, glycerol, and dextrose. Suitable buffers include, but are not limited to, phosphate and citrate. Suitable antioxidants are those as described herein, including bisulfite and sodium metabisulfite. Suitable local anesthetics include, but are not limited to, procaine hydrochloride. Suitable suspending and dispersing agents are those as described herein, including sodium carboxymethylcellulose, hydroxypropylmethylcellulose, and polyvinylpyrrolidone. Suitable emulsifiers are those as described herein, including polyoxyethylene sorbitan monolaurate, polyoxyethylene sorbitan monooleate 80, and triethanolamine oleate. Combination of Chinese herbs Suitable masking or chelating agents include, but are not limited to, EDTA. Suitable pH adjusters include, but are not limited to, sodium hydroxide, hydrochloric acid, citric acid, and lactic acid. Suitable complexing agents include, but are not limited to, cyclodextrins, including alpha-cyclodextrin, beta-cyclodextrin, hydroxypropyl-beta-cyclodextrin, sulfobutyl ether-beta-cyclodextrin, and sulfobutyl ether 7-beta-cyclodextrin ((S))

CyDex,Lenexa,KS)。

When the pharmaceutical compositions provided herein are formulated for multiple dose administration, the multiple dose parenteral formulations must contain an antimicrobial agent at a bacteriostatic or fungistatic concentration. All parenteral formulations must be sterile, as is known and practiced in the art.

In one embodiment, the pharmaceutical composition for parenteral administration is provided as a ready-to-use sterile solution. In another embodiment, the pharmaceutical composition is provided as a sterile, dry, soluble product, including lyophilized powders and hypodermic tablets, which are reconstituted with the vehicle immediately prior to use. In yet another embodiment, the pharmaceutical composition is provided as a ready-to-use sterile suspension. In yet another embodiment, the pharmaceutical composition is provided as a sterile, dry, insoluble product that is reconstituted with a vehicle immediately prior to use. In yet another embodiment, the pharmaceutical composition is provided as a sterile emulsion ready for use.

Pharmaceutical compositions provided herein for parenteral administration may be formulated in immediate release or modified release dosage forms, including delayed release, sustained release, pulsed release, controlled release, targeted release, and programmed release forms.

Pharmaceutical compositions provided herein for parenteral administration may be formulated as suspensions, solids, semi-solids, or thixotropic liquids for administration as an implanted depot. In one embodiment, the pharmaceutical compositions provided herein are dispersed in a solid inner matrix surrounded by an outer polymer film that is insoluble in body fluids but allows diffusion of the active ingredient in the pharmaceutical composition therethrough.

Suitable internal matrices include, but are not limited to, polymethylmethacrylate, polybutylmethacrylate, plasticized or unplasticized polyvinyl chloride, plasticized nylon, plasticized polyethylene terephthalate, natural rubber, polyisoprene, polyisobutylene, polybutadiene, polyethylene, ethylene vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, silicone carbonate copolymers, hydrophilic polymers (e.g., hydrogels of esters of acrylic and methacrylic acids), collagen, crosslinked polyvinyl alcohol, and crosslinked partially hydrolyzed polyvinyl acetate.

Suitable outer polymeric films include, but are not limited to, polyethylene, polypropylene, ethylene/propylene copolymers, ethylene/ethyl acrylate copolymers, ethylene/vinyl acetate copolymers, silicone rubber, polydimethylsiloxane, neoprene, chlorinated polyethylene, polyvinyl chloride, copolymers of vinyl chloride and vinyl acetate, vinylidene chloride, ethylene and propylene ionomers, polyethylene terephthalate, butyl rubber, epichlorohydrin rubber, ethylene/vinyl alcohol copolymers, ethylene/vinyl acetate/vinyl alcohol terpolymers, and ethylene/ethyleneoxyethanol copolymers.

C. Modified release

The pharmaceutical compositions provided herein can be formulated as modified release dosage forms. As used herein, the term "modified release" refers to a dosage form wherein the rate or location of release of the active ingredient is different from that of an immediate release dosage form when administered by the same route. Modified release dosage forms include, but are not limited to, delayed release, extended release, sustained release, pulsatile release, controlled release, accelerated release, rapid release, targeted release, programmed release, and gastric retentive dosage forms. The pharmaceutical compositions of the modified release dosage forms may be prepared using a variety of modified release devices and methods known to those skilled in the art, including, but not limited to, matrix controlled release devices, osmotic controlled release devices, multiparticulate controlled release devices, ion exchange resins, enteric coatings, multilayer coatings, microspheres, liposomes, and combinations thereof. The release rate of the active ingredient can also be varied by varying the particle size and polymorphism of the active ingredient.

Examples of modified release include, but are not limited to, those described in the following U.S. patents: 3,845,770; 3,916,899; 3,536,809, respectively; 3,598,123, respectively; 4,008,719, respectively; 5,674,533, respectively; 5,059,595, respectively; 5,591,767, respectively; 5,120,548, respectively; 5,073,543, respectively; 5,639,476, respectively; 5,354,556, respectively; 5,639,480, respectively; 5,733,566; 5,739,108, respectively; 5,891,474, respectively; 5,922,356, respectively; 5,972,891, respectively; 5,980,945, respectively; 5,993,855, respectively; 6,045,830, respectively; 6,087,324, respectively; 6,113,943; 6,197,350, respectively; 6,248,363, respectively; 6,264,970, respectively; 6,267,981, respectively; 6,376,461, respectively; 6,419,961, respectively; 6,589,548, respectively; 6,613,358, respectively; and 6,699,500.

Also provided herein are kits that, when used by a physician, can simplify administration of appropriate amounts of the active ingredients to a subject. In certain embodiments, the kits provided herein comprise one or more containers and a dosage form of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a BTK inhibitor.

In certain embodiments, the kits provided herein comprise one or more containers and a dosage form of a compound of formula (I) or an isotopic variant thereof, or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, and a BTK inhibitor. The kits provided herein can further comprise a device for administering the active ingredient. Examples of such devices include, but are not limited to, syringes and needleless syringe drip bags.

The kits provided herein can further include a pharmaceutically acceptable vehicle that can be used to administer one or more active ingredients. For example, if the active ingredient is provided in a solid form that must be reconstituted for parenteral administration, the kit may include a sealed container of a suitable vehicle in which the active ingredient may be dissolved to form a sterile, particulate-free solution suitable for parenteral administration. Examples of pharmaceutically acceptable vehicles include, but are not limited to: aqueous vehicles including, but not limited to, water for injection USP, sodium chloride injection, ringer's injection, dextrose and sodium chloride injection, and lactated ringer's injection; water-miscible vehicles including, but not limited to, ethanol, polyethylene glycol, and polypropylene glycol; and non-aqueous vehicles including, but not limited to, corn oil, cottonseed oil, peanut oil, sesame oil, ethyl oleate, isopropyl myristate, and benzyl benzoate.

The disclosure will be further understood by the following non-limiting examples.

Examples

As used herein, the symbols and conventions used in the procedures, schemes and examples, whether or not specific abbreviations are specifically defined, are consistent with those used in the scientific literature of the present day, such as the Journal of the American Chemical Society or the Journal of Biological Chemistry. In particular, but not by way of limitation, the following abbreviations may be used in the examples and throughout the specification: g (grams); mg (milligrams); mL (milliliters); μ L (microliters); m (mole); mM (millimolar concentration); μ M (micromolar concentration); eq. (eq); mmol (millimole); hz (hertz); MHz (megahertz); hr or hrs (hours); min (minutes); and MS (mass spectrometry).

For all the examples below, standard work-up and purification methods known to the person skilled in the art can be used. Unless otherwise indicated, all temperatures are expressed in degrees Celsius. All reactions were carried out at room temperature unless otherwise indicated. The synthetic methods described herein are intended to exemplify applicable chemistry by using specific examples and do not represent the scope of the disclosure.

The synthesis of compound I is described in us patent 9,056,852B2, which is incorporated by reference into these disclosures.

Example 1: 4- (2- (difluoromethyl) -1H-benzo [ d ]]Synthesis of imidazol-1-yl) -N- (2-methyl-1- (2- (1-methylpiperidin-4-yl) phenyl) propan-2-yl) -6-morpholino-1, 3, 5-triazin-2-amine (Compound I)

Reacting 4- (2- (difluoromethyl) -1H-benzo [ d ]]A mixture of imidazol-1-yl) -N- (2-methyl-1- (2- (piperidin-4-yl) phenyl) propan-2-yl) -6-morpholino-1, 3, 5-triazin-2-amine (80mg, 0.14mmol), aqueous formaldehyde (37%, 23mg) and sodium cyanoborohydride (11mg, 0.17mmol) in methanol (2mL) was stirred at room temperature for 1 hour. The crude product was purified by preparative HPLC to give compound I as a white solid (11mg, 13% yield): 99% purity (HPLC); MS M/z 577.3(M + 1); ¹H NMR(CDCl₃,500MHz)8.37(d,1H),7.90(d,1H),7.64(t,1H),7.42(m,2H),7.32(d,1H),7.24(1,1H),7.13(t,1H),7.07(d,1H),5.15(s,1H),4.00-3.70(m,8H),3.28(s,2H),2.94(m,2H),2.78(m,2H),2.28(s,3H),1.891.60(m,6H),1.53(s,6H)ppm。

Example 2: combinatorial study

The activity of compound I in combination with PCI-32765 (ibrutinib) was examined in a set of 8 DLBCL cell lines (7 GCB subtype cell lines and 1 ABC subtype cell line) shown below.

TABLE 1

ATPLite test

The effect of the test compounds and combinations on growth inhibition as a measure of cell viability was determined in the applite assay. The endpoint readings for this assay are based on the quantification of ATP as an indicator of viable cells.

Cells were thawed from liquid nitrogen storage. Screening begins once the cells expand and divide at their expected doubling time. Cells were seeded at 500 cells/well in growth medium in black 384-well tissue culture treatment plates (except where recorded in the analyzer). Cells were equilibrated in assay plates via centrifugation and placed in a 37 ℃ incubator attached to a dosing module for 24 hours prior to processing. At the time of treatment, a panel of assay plates (not treated) was collected and ATP levels were determined by addition of applite (Perkin Elmer). These T-zeros (T-zeros) were read using ultrasensitive luminescence on Envision Plate Readers₀) And (3) a plate. The treated assay plates were incubated with the compounds for 72 hours. All data points are collected via an automated process; controlling the quality; and analyzed using Horizon Discovery proprietary software. The assay plate is accepted if it passes the following quality control criteria: relative luciferase values were consistent throughout the experiment, with a Z-factor score greater than 0.6, and untreated/vehicle controls performed consistently on the plates.

Growth Inhibition (GI) was used as a measure of cell viability.At the time of administration (T)₀) And 72 hours later (T)₇₂) The cell viability of the vehicle was measured. GI reading of 0% indicates no growth inhibition-cells treated with compound and T₇₂Or T₁₂₀The vehicle signals match. GI 100% represents complete growth inhibition-cells treated with compound and T_oThe vehicle signals match. In wells with GI of 100%, the cell number did not increase during treatment and could suggest a cytostatic effect of the compound at which level plateau is reached. A GI of 200% indicates complete death of all cells in the culture well. Compounds that reached an activity plateau of GI 200% were considered cytotoxic. GI was calculated by applying the following check sum equation:

if T is less than V₀：

If T is greater than or equal to V₀：

Where T is the signal measurement for the test, V is the measurement for the vehicle-treated control, and V₀Is a measurement of the vehicle control at time zero. This formula is derived from National Cancer Institute's [ sic ]]NCl[sic]Growth inhibition calculations used in 60 high throughput screening.

FIGS. 1-8 provide the signalling agent dose response curves for growth inhibition by Compound I in the cell lines shown in Table 1.

As shown in figure 9, compound I has different levels of activity in the cell line group. All cell lines reach>50% growth inhibition level, median GI₅₀It was 1.73. mu.M.

As shown in FIG. 10, Compound I induced a cytotoxic effect in 3 cell lines (DOHH-2, OCI-Ly3 and OCI-Ly19) and a sub-cytostatic effect in 3 cell lines (SU-DIAL-10, Pfeiffer and NU-DHL-1).

Loewe accumulation model

The effect of the drug combination was determined using the Loewe additive model. The Loewe additive model is dose-based and is only applicable to the level of activity achieved with a single drug. Loewe Volume was used to evaluate the overall magnitude of combined interactions over the Loewe accumulation model. Loewe Volume is particularly useful when differentiating synergistic increases in phenotypic activity (positive Loewe Volume) versus synergistic antagonism (negative Loewe Volume). When antagonism is observed, Loewe Volume should be evaluated to examine whether there is any correlation between antagonism and the activity of a particular drug target or cell genotype. The model defines additive as non-synergistic combination interactions where the combined dose matrix surface should be indistinguishable from any drug that crosses itself. The calculation for additivity is:

Satisfy (X/X)_I)+(Y/Y_I) 1-1 of_Loewe

Wherein X_IAnd Y_IIs the single agent effective concentration of the observed combined effect I. For example, if 1mM drug A or 1mM drug B, respectively, achieve 50% inhibition, the combination of 0.5mM A and 0.5mM B should also inhibit 50%.

Synergy scoring

To measure the combined effect over Loewe additivity, a scale measure was designed to characterize the strength of synergistic interaction and is referred to as a synergy score. Synergy scores were calculated as follows:

synergy score log f_X log f_YΣmax(0,I_data)(I_data–I_Loewe)

Fractional inhibition for each component agent and combination point in the matrix was calculated relative to the median of all vehicle-treated control wells. The synergy scoring equation integrates the experimentally observed active volume at each point in the matrix beyond the model surface derived numerically from the activity of the component agents using the Loewe additive model. Other terms in the synergy score equation (above) were used to normalize for various dilution factors for each agent and allow for the synergy scores to be compared throughout the experiment. Positive inhibition gating or I_dataThe introduction of the multiplier eliminates noise near the zero effect level,and eliminates the bias caused by synergistic interactions that occur at high activity levels.

An isogram was used to evaluate the shift in efficacy, which demonstrates how much less drug is required in the combination to achieve the level of effect than the amount of single agent required to achieve the desired effect. An iso-effect plot is drawn by determining the concentration trace corresponding to the inhibition level indicated by the crossover. This is accomplished by finding the intersection of each single drug concentration with the other single drug concentrations in the dose matrix. In practice, each vertical concentration C will be_YHeld fixed, while a bisection algorithm is used to determine the level concentration C that achieves a selected level of effect in the response surface Z (CX, CY)_XIn combination with a vertical dose. These concentrations were then concatenated by linear interpolation to produce an isobologram display. For synergistic interactions, the isobologram falls from the line below the accumulation threshold and near the origin, while antagonistic interactions will lie above the accumulation threshold. The error bars represent the uncertainty that each data point used to generate the iso-plot yields. Finding Z-sigma by using dichotomy_Z(C_X,C_Y) And Z + sigma_Z(C_X,C_Y) And I_cutConcentration at crossover, uncertainty of each crossover point estimated by response error, where σ_ZIs the standard deviation of the residual error on the effect scale.

The synergy scores for the test combinations are provided in table 2 below.

In certain embodiments, a synergy score of 0 is an additive result. In certain embodiments, a synergy score of 0 to 2 may be considered additive or just above additive. In certain embodiments, the higher the synergy score, the greater the synergy outcome for both agents.

Table 2:

as can be seen from the data, a strong activity breadth of the combination of compound I and ibrutinib was observed in the GCB-DLBCL cell line. A strong synergistic effect of ibrutinib was observed in the DOHH-2 cell line.

The examples set forth above are provided to give those of ordinary skill in the art a complete disclosure and description of how to make and use the claimed embodiments, and are not intended to limit the scope of what is disclosed herein. Modifications apparent to those skilled in the art will fall within the scope of the following claims.

Example 3: study of combinations of PI3K inhibitors with ibrutinib in Chronic Lymphocytic Leukemia (CLL) patients

The aim of this study was to evaluate the safety and efficacy of compounds I, II, III or IV (3 doses: 60 mg/day, 120 mg/day and 150 mg/day) and ibrutinib in CLL patients.

Evaluation indexes of main results are as follows: determination of acceptable adverse events associated with treatment [ time frame: 6 months of treatment ]. The incidence of adverse events, any potential laboratory abnormalities and any dose-limiting toxicity were determined.

Secondary result evaluation index: overall reaction rate [ time range: 1 year at the longest. Overall Response Rate (ORR) in CLL patients treated with a combination of compound I, II, III or IV and ibrutinib.

Patients should not be exposed to the compound prior to entering the study. Patients were not treated for their cancer within 2 weeks of the start of the trial. Treatment includes the use of chemotherapy, hematopoietic growth factors and biological therapies such as monoclonal antibodies. Patients must have recovered from all toxicities associated with prior treatments (to grade 0 or 1). Safety was assessed for all subjects and all blood collections for pharmacokinetic analysis were collected on a schedule. All studies were performed with institutional ethics committee approval and patient consent.

The dose of the compound may be maintained or modified for toxicity based on the evaluation outlined below. Treatment was repeated every 28 days in the absence of unacceptable toxicity. Dose-limiting toxicity was determined according to the definitions and criteria set by the National Cancer Institute (NCI) common term for adverse events (CTCAE) version 3.0 (8/9 2006).

Blood was sampled by direct venipuncture to sample continuous blood before and after administration of the compound. Venous blood samples (5mL) for determination of serum concentration were obtained about 10 minutes prior to dosing and at about days 1, 8 and 15 post-dosing. Each serum sample was divided into two equal parts. All serum samples were stored at-20 ℃. Serum samples were shipped on dry ice.

Pharmacokinetics: patients underwent plasma/serum sample collection for pharmacokinetic evaluation prior to initiation of treatment and on days 1, 8, and 15. Pharmacokinetic parameters were calculated by a model independent method using the latest version of BIOAVL software on a Digital Equipment Corporation VAX 8600 computer system. The following pharmacokinetic parameters were determined: peak serum concentration (C)_max) (ii) a Time to peak serum concentration (t)_max) (ii) a Area under concentration-time curve (AUC) from time point zero to time of last blood sample calculated using the Linear trapezoidal rule_0-72) (ii) a And a terminal elimination half-life (t) calculated from the elimination rate constant_1/2). The elimination rate constant was estimated by linear regression of consecutive data points in the terminal linear region of the log-linear concentration-time plot. For each treatment, the mean, Standard Deviation (SD) and Coefficient of Variation (CV) of the pharmacokinetic parameters were calculated. The ratio of the mean values of the parameters (retained formulation/non-retained formulation) was calculated.

Patient response to combination therapy: the patient's response is assessed via imaging with X-rays, CT scans and MRI, and imaging is performed before the study begins and at the end of the first cycle, with additional imaging performed every four weeks or at the end of subsequent cycles. The imaging modality is selected based on the cancer type and feasibility/availability and the same imaging modality is used for similar cancer types and throughout the study for each patient. Patient response is also assessed by complete blood cell count and/or bone marrow biopsy. Response rates were determined using RECIST criteria. (Therasse et al, J.Natl. cancer Inst.2000, 2.2.2; 92(3): 205-16; http:// ctep.cancer. gov/forms/therraseseRECIST JNCI. pdf). Patients were followed up regularly for 4 weeks after study treatment was completed.

Example 4:study of PI3K inhibitor in combination with BGB-3111 in patients with relapsed refractory diffuse large B-cell lymphoma (r/r DLBCL)

The purpose of this study was to evaluate the safety and efficacy of compound I, II, III or IV (3 doses: 30 mg/day, 45 mg/day and 60 mg/day) and BGB-3111 in r/r DLBCL patients.

Evaluation indexes of main results are as follows: determination of acceptable adverse events associated with treatment [ time frame: 6 months of treatment ]. The incidence of adverse events, any potential laboratory abnormalities and any dose-limiting toxicity were determined.

Secondary result evaluation index: overall reaction rate [ time range: 1 year at the longest. Overall Response Rate (ORR) in r/r DLBCL patients treated with a combination of compound I, II, III or IV and BGB-3111.

Patients should not be exposed to the compound prior to entering the study. Patients were not treated for their cancer within 2 weeks of the start of the trial. Treatment includes the use of chemotherapy, hematopoietic growth factors and biological therapies such as monoclonal antibodies. Patients must have recovered from all toxicities associated with prior treatments (to grade 0 or 1). Safety was assessed for all subjects and all blood collections for pharmacokinetic analysis were collected on a schedule. All studies were performed with institutional ethics committee approval and patient consent.

The dose of the compound may be maintained or modified for toxicity based on the evaluation outlined below. Treatment was repeated every 28 days in the absence of unacceptable toxicity. Dose-limiting toxicity was determined according to the definitions and criteria set by the National Cancer Institute (NCI) common term for adverse events (CTCAE) version 3.0 (8/9 2006).

Blood was sampled by direct venipuncture to sample continuous blood before and after administration of the compound. Venous blood samples (5mL) for determination of serum concentration were obtained about 10 minutes prior to dosing and at about days 1, 8 and 15 post-dosing. Each serum sample was divided into two equal parts. All serum samples were stored at-20 ℃. Serum samples were shipped on dry ice.

Pharmacokinetics: patients underwent plasma/serum sample collection for pharmacokinetic evaluation prior to initiation of treatment and on days 1, 8, and 15. Pharmacokinetic parameters were calculated by a model independent method using the latest version of BIOAVL software on a Digital Equipment Corporation VAX 8600 computer system. The following pharmacokinetic parameters were determined: peak serum concentration (C)_max) (ii) a Time to peak serum concentration (t)_max) (ii) a Area under concentration-time curve (AUC) from time point zero to time of last blood sample calculated using the Linear trapezoidal rule _0-72) (ii) a And a terminal elimination half-life (t) calculated from the elimination rate constant_1/2). The elimination rate constant was estimated by linear regression of consecutive data points in the terminal linear region of the log-linear concentration-time plot. For each treatment, the mean, Standard Deviation (SD) and Coefficient of Variation (CV) of the pharmacokinetic parameters were calculated. The ratio of the mean values of the parameters (retained formulation/non-retained formulation) was calculated. Patient response to combination therapy: the patient's response is assessed via imaging with X-rays, CT scans and MRI, and imaging is performed before the study begins and at the end of the first cycle, with additional imaging performed every four weeks or at the end of subsequent cycles. The imaging modality is selected based on the cancer type and feasibility/availability and the same imaging modality is used for similar cancer types and throughout the study for each patient. Patient response is also assessed by complete blood cell count and/or bone marrow biopsy. Response rates were determined using RECIST criteria. (Therasse et al, J.Natl. cancer Inst.2000, 2.2.2; 92(3): 205-16; http:// ctep.cancer. gov/forms/therraseseRECIST JNCI. pdf). Patients were followed up regularly for 4 weeks after study treatment was completed.

Claims (62)

1. A method of treating or preventing cancer, comprising administering to a subject in need thereof:

(i) about 30mg, about 45mg or about 60mg of a compound of formula (I):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

x, Y and Z are each independently N or CR^XProvided that at least two of X, Y and Z are nitrogen atoms; wherein R is^XIs hydrogen or C_1-6An alkyl group;

R¹and R²Each independently is (a) hydrogen, cyano, halo, or nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (C) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c(ii) a Wherein each R^1a、R^1b、R^1cAnd R^1dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^1bAnd R^1cTogether with the N atom to which they are attached form a heterocyclyl;

R³and R⁴Each independently is hydrogen or C_1-6An alkyl group; or R³And R⁴Are connected together to form a bond, C_1-6Alkylene radical, C_1-6Heteroalkylidene radical, C_2-6Alkenylene or C_2-6A heteroalkenylene group;

R^5ais (a) hydrogen or halo; (b) c _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (C) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (C) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5cIs- (CR)^5fR^5g)_n–(C_6-14Aryl) or- (CR^5fR^5g)_n-a heteroaryl group;

R^5dand R^5eEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (C) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c；

R^5fAnd R^5gEach independently is (a) hydrogen or halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (C) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1c(ii) a or-S (O)₂NR^1bR^1c(ii) a Or (d) when one is present R^5fAnd one present R^5gWhen attached to the same carbon atom, said R^5fAnd R^5gTogether with the carbon atom to which they are attached form C_3–10Cycloalkyl or heterocyclyl;

R⁶is hydrogen, C_1-6Alkyl, -S-C_1-6Alkyl, -S (O) -C_1-6Alkyl or-SO₂–C_1-6An alkyl group;

m is 0 or 1; and is

n is 0, 1, 2, 3 or 4;

wherein R is¹、R²、R³、R⁴、R⁶、R^X、R^1a、R^1b、R^1c、R^1d、R^5a、R^5b、R^5c、R^5d、R^5e、R^5fAnd R^5gEach alkyl, alkylene, heteroalkylene, alkenyl, alkenylene, heteroalkenylene, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl group of (a) is optionally substituted with one, two, three, four, or five substituents Q, wherein each substituent Q is independently selected from (a) oxo, cyano, halo, and nitro; (b) c _1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl, each of which is further optionally substituted by one, two, three or four substituents Q^aSubstituted; and (C) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cand-S (O)₂NR^bR^cWherein each R is^a、R^b、R^cAnd R^dIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is further optionally substituted by one, two, three or four substituents Q^aSubstituted; or (iii) R^bAnd R^cTogether with the N atom to which they are attached form a heterocyclic group which is further optionally substituted by one, two, three or four substituents Q^aSubstituted;

wherein each Q^aIndependently selected from (a) oxo, cyano, halo and nitro; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl and heterocyclyl; and (C) -C (O) R^e、–C(O)OR^e、–C(O)NR^fR^g、–C(NR^e)NR^fR^g、–OR^e、–OC(O)R^e、–OC(O)OR^e、–OC(O)NR^fR^g、–OC(＝NR^e)NR^fR^g、–OS(O)R^e、–OS(O)₂R^e、–OS(O)NR^fR^g、–OS(O)₂NR^fR^g、–NR^fR^g、–NR^eC(O)R^h、–NR^eC(O)OR^h、–NR^eC(O)NR^fR^g、–NR^eC(＝NR^h)NR^fR^g、–NR^eS(O)R^h、–NR^eS(O)₂R^h、–NR^eS(O)NR^fR^g、–NR^eS(O)₂NR^fR^g、–SR^e、–S(O)R^e、–S(O)₂R^e、–S(O)NR^fR^gand-S (O)₂NR^fR^g(ii) a Wherein each R^e、R^f、R^gAnd R^hIndependently (i) hydrogen; (ii) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (iii) R^fAnd R^gTogether with the N atom to which they are attached form a heterocyclyl;

wherein two substituents Q adjacent to each other optionally form C _3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; and

(ii) about 160mg or about 320mg BGB-3111 or a pharmaceutically acceptable salt thereof,

wherein a compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, is administered to the subject once daily; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

2. The method of claim 1, wherein R^5bIs (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl or heteroaryl; or (C) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–S(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c。

3. The method of claim 1, wherein R^5aAnd R^5bEach independently is (a) halo; (b) c_1-6Alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl; or (C) -C (O) R^1a、–C(O)OR^1a、–C(O)NR^1bR^1c、–C(NR^1a)NR^1bR^1c、–OR^1a、–OC(O)R^1a、–OC(O)OR^1a、–OC(O)NR^1bR^1c、–OC(＝NR^1a)NR^1bR^1c、–OS(O)R^1a、–OS(O)₂R^1a、–OS(O)NR^1bR^1c、–OS(O)₂NR^1bR^1c、–NR^1bR^1c、–NR^1aC(O)R^1d、–NR^1aC(O)OR^1d、–NR^1aC(O)NR^1bR^1c、–NR^1aC(＝NR^1d)NR^1bR^1c、–NR^1aS(O)R^1d、–NR^1aS(O)₂R^1d、–NR^1aS(O)NR^1bR^1c、–NR^1aS(O)₂NR^1bR^1c、–SR^1a、–S(O)R^1a、–S(O)₂R^1a、–S(O)NR^1bR^1cor-S (O)₂NR^1bR^1c。

4. The method of claim 3, wherein R^5aAnd R^5bEach is methyl optionally substituted with one, two or three halo.

5. The method of any one of claims 1-4, wherein n is 1.

6. The method of any one of claims 1-5, wherein R^5fAnd R^5gEach is hydrogen.

7. The method of any one of claims 1-4, wherein n is 0.

8. The method of any one of claims 1-7, wherein m is 0.

9. The method of any one of claims 1-8, wherein the compound of formula (I) is a compound of formula (XI):

or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; wherein:

R^7a、R^7b、R^7c、R^7dand R^7eEach independently is (a) hydrogen, cyano, halo, or nitro;(b)C_1-6alkyl radical, C_2-6Alkenyl radical, C_2-6Alkynyl, C_3-10Cycloalkyl radical, C_6-14Aryl radical, C_7-15Aralkyl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aSubstituted; or (C) -C (O) R^a、–C(O)OR^a、–C(O)NR^bR^c、–C(NR^a)NR^bR^c、–OR^a、–OC(O)R^a、–OC(O)OR^a、–OC(O)NR^bR^c、–OC(＝NR^a)NR^bR^c、–OS(O)R^a、–OS(O)₂R^a、–OS(O)NR^bR^c、–OS(O)₂NR^bR^c、–NR^bR^c、–NR^aC(O)R^d、–NR^aC(O)OR^d、–NR^aC(O)NR^bR^c、–NR^aC(＝NR^d)NR^bR^c、–NR^aS(O)R^d、–NR^aS(O)₂R^d、–NR^aS(O)NR^bR^c、–NR^aS(O)₂NR^bR^c、–SR^a、–S(O)R^a、–S(O)₂R^a、–S(O)NR^bR^cor-S (O)₂NR^bR^c(ii) a Or

R^7a、R^7b、R^7c、R^7dAnd R^7eTwo of which are adjacent to each other form C_3-10Cycloalkenyl radical, C_6-14Aryl, heteroaryl or heterocyclyl, each of which is optionally substituted by one, two, three or four substituents Q^aAnd (4) substituting.

10. The method of any one of claims 1-9, wherein the compound of formula (I) is compound I:

Isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

11. The method of any one of claims 1-9, wherein the compound of formula (I) is compound II:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

12. The method of any one of claims 1-9, wherein the compound of formula (I) is compound III:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

13. The method of any one of claims 1-9, wherein the compound of formula (I) is compound IV:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

14. The method of any one of claims 1-9, wherein the compound of formula (I) is compound V:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

15. The method of any one of claims 1-9, wherein the compound of formula (I) is compound VI:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

16. The method of any one of claims 1-9, wherein the compound of formula (I) is compound VII:

Isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

17. The method of any one of claims 1-9, wherein the compound of formula (I) is compound VIII:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

18. The method of any one of claims 1-9, wherein the compound of formula (I) is compound IX:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

19. The method of any one of claims 1-9, wherein the compound of formula (I) is compound X:

isotopic variations thereof, pharmaceutically acceptable salts, solvates, hydrates, or prodrugs thereof.

20. The method of any one of the preceding claims, wherein the cancer is a hematologic malignancy.

21. The method of any one of the preceding claims, wherein the cancer is a B cell malignancy.

22. The method of any one of the preceding claims, wherein the cancer is Acute Lymphoblastic Leukemia (ALL), Acute Myeloid Leukemia (AML), Chronic Myeloid Leukemia (CML), acute monocytic leukemia (AMoL), Chronic Lymphocytic Leukemia (CLL), high risk Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, nodal marginal zone B-cell lymphoma, burkitt's lymphoma, non-burkitt high grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, precursor B-lymphoblastic lymphoma, Acute Myelogenous Leukemia (AML), acute monocytic leukemia (CML), acute monocytic leukemia (AMoL), Chronic Lymphocytic Leukemia (CLL), high risk Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), follicular lymphoma (, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma or lymphomatoid granulomatosis.

23. The method of any one of the preceding claims, wherein the cancer is chronic lymphocytic leukemia or non-hodgkin's lymphoma.

24. The method of any one of the preceding claims, wherein the cancer is non-hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL).

25. The method of any one of the preceding claims, wherein the cancer is relapsed refractory diffuse large B-cell lymphoma (r/r DLBCL).

26. The method of claim 24 or 25, wherein the diffuse large B-cell lymphoma is activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) or germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL).

27. The method of any one of the preceding claims, wherein about 30mg of a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, is administered to the subject; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

28. The method of any one of claims 1-26, wherein about 45mg of a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, is administered to the subject; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

29. The method of any one of claims 1-26, wherein about 60mg of a compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, is administered to the subject; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

30. The method of any one of claims 1-29, wherein about 160mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject.

31. The method of any one of claims 1-29, wherein about 320mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject.

32. The method of any one of claims 1-31, wherein BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily or twice daily.

33. The method of any one of claims 1-31, wherein BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily.

34. The method of any one of claims 1-31, wherein BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject twice daily.

35. The method of any one of claims 1-31, wherein about 160mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject twice daily.

36. The method of any one of claims 1-31, wherein about 320mg BGB-3111, or a pharmaceutically acceptable salt thereof, is administered to the subject once daily.

37. The method of any one of claims 1-36, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof, is administered simultaneously, substantially simultaneously, or sequentially in any order; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and BGB-3111 or a pharmaceutically acceptable salt thereof.

38. The method of any one of claims 1-36, wherein the compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, is administered simultaneously or substantially simultaneously; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and BGB-3111 or a pharmaceutically acceptable salt thereof.

39. The method of any one of claims 1-36, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, and BGB-3111 or a pharmaceutically acceptable salt thereof.

40. The method of claim 39, wherein the compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, is administered prior to BGB-3111, or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

41. The method of claim 39, wherein the compound of formula (I), or an enantiomer, mixture of enantiomers, mixture of two or more diastereomers, or isotopic variant thereof, is administered after BGB-3111, or a pharmaceutically acceptable salt thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof.

42. The method of any one of the preceding claims, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof, is formulated as a tablet or capsule.

43. The method according to any one of the preceding claims, wherein BGB-3111, or a pharmaceutically acceptable salt thereof, is formulated as a tablet or capsule.

44. The method of any one of claims 1-38, wherein the compound of formula (I), or an enantiomer, a mixture of enantiomers, a mixture of two or more diastereomers, or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate or prodrug thereof, is co-formulated with BGB-3111 or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition comprising compound I:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

46. A pharmaceutical composition comprising compound II:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

47. A pharmaceutical composition comprising compound III:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

48. A pharmaceutical composition comprising compound IV:

Or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

49. A pharmaceutical composition comprising compound V:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

50. A pharmaceutical composition comprising compound VI:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

51. A pharmaceutical composition comprising compound VII:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

52. A pharmaceutical composition comprising compound VIII:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

53. A pharmaceutical composition comprising compound IX:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

54. A pharmaceutical composition comprising compound X:

or an isotopic variant thereof; or a pharmaceutically acceptable salt, solvate, hydrate, or prodrug thereof; BGB-3111 or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable excipient.

55. A method of treating or preventing cancer, comprising administering to a subject in need thereof an effective amount of the pharmaceutical composition of any one of claims 45-54.

56. The method of claim 55, wherein the cancer is a hematologic malignancy.

57. The method of claim 55, wherein the cancer is a B cell malignancy.

58. The method of claim 55, wherein the cancer is Acute Lymphoblastic Leukemia (ALL), Acute Myelogenous Leukemia (AML), Chronic Myelogenous Leukemia (CML), acute monocytic leukemia (AMoL), Chronic Lymphocytic Leukemia (CLL), high risk Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Mantle Cell Lymphoma (MCL), Waldenstrom's macroglobulinemia, multiple myeloma, extranodal marginal zone B-cell lymphoma, Burkitt's lymphoma, non-Burkitt high grade B-cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B lymphoblastic lymphoma, Acute Myelogenous Leukemia (AML), Acute Monocytic Leukemia (AML), Chronic Lymphocytic Leukemia (CLL), high risk Chronic Lymphocytic Leukemia (CLL), Small Lymphocytic Lymphoma (SLL), high risk Small Lymphocytic Lymphoma (SLL), Follicular Lymphoma (FL), b cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma or lymphomatoid granulomatosis.

59. The method of claim 55, wherein the cancer is chronic lymphocytic leukemia or non-Hodgkin's lymphoma.

60. The method of claim 55, wherein the cancer is non-Hodgkin's lymphoma, diffuse large B-cell lymphoma (DLBCL).

61. The method of claim 55, wherein the cancer is relapsed refractory diffuse large B-cell lymphoma (r/r DLBCL).

62. The method of claim 60 or 61, wherein the diffuse large B-cell lymphoma is activated B-cell diffuse large B-cell lymphoma (ABC DLBCL) or germinal center B-cell diffuse large B-cell lymphoma (GCB DLBCL).

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